Pharmaceutical compositions and dosage forms

ABSTRACT

Disclosed herein are pharmaceutical compositions and dosage forms including N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino) benzamide that are useful in the treatment of subjects having cancer. The present disclosure also provides methods for preparing these pharmaceutical compositions and dosage forms, and methods of treating subjects having cancer utilizing the pharmaceutical compositions and dosage forms provided herein.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of and priority to U.S. ProvisionalPatent Application No. 62/534,585, filed Jul. 19, 2017, the contents ofwhich are hereby incorporated by reference herein in their entirety.

FIELD

The present disclosure relates to pharmaceutical compositions and dosageforms that are useful in the treatment of subjects having cancer. Thepresent disclosure also provides methods for preparing thesepharmaceutical compositions and dosage forms, and methods of treatingsubjects having cancer utilizing the pharmaceutical compositions anddosage forms provided herein.

BACKGROUND

The compoundN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideand its preparation have been disclosed in U.S. Pat. No. 8,299,057, thecontents of which are hereby incorporated by reference in theirentirety.N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideis a potent inhibitor of tyrosine kinases, NTRK1/2/3-transformingtyrosine kinase proteins (TrkA, TrkB, TrkC), proto-oncogenetyrosine-protein kinase 1 (ROS1), and anaplastic lymphoma kinase (ALK).In various in vitro studies,N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideinhibited proliferation of the CRC cell line KM12, which depends uponTrkA kinase activity for proliferation and survival. It was also potentin inhibiting cell proliferation of ALK-dependent Anaplastic Large CellLymphoma cell lines.

In a single-dose food effect study in dogs ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide,in a formulation that did not comprise at least one acidulant, exposurelevels ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidein the dogs were approximately 2-fold higher under fed conditionscompared to those observed under fasting conditions. Such food effectscan cause difficulty during human testing of drugs as the fed or fastedcondition of the patient can cause exposure or bioavailability of drugsto vary widely.

In early clinical studies in humans,N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidehas been shown to have antitumor effects in patients having variousforms of cancer having at least one molecular alteration in one or moreof ALK, ROS1, TrkA, TrkB and TrkC. In the studies using a formulation ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidethat did not comprise at least one acidulant, systemic exposure ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideincreased when co-administered with food. In particular,N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideAUC values were approximately 200% and 50% higher usingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidedoses of 200 mg/m²/day and 400 mg/m²/day, respectively when taken withfood. Cmax values were approximately 150% higher with food for bothdoses. In addition, some patients in these studies receivedN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideand concomitant proton pump inhibitor drugs (PPIs), such aslansoprazole, and demonstrated variableN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideexposures. Moreover, dose proportionality was lost at doses higher than800 mg/m²/day. As such, it is an object of the present disclosure toprovide pharmaceutical compositions and dosage forms comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidethat do not suffer from the variability in absorption in subjects, suchas humans, when dosed with or without food and in the presence orabsence of PPIs.

SUMMARY

In some embodiments are provided pharmaceutical compositions, comprisinga weakly basic organic compound and at least one acidulant. In someembodiments, the at least one acidulant is an organic acidulant. In someembodiments, the at least one acidulant is selected from tartaric acid,maleic acid, fumaric acid, citric acid, and betaine hydrochloride. Insome embodiments, the at least one acidulant is fumaric acid. In someembodiments, the at least one acidulant is tartaric acid. In someembodiments, the said at least one acidulant is maleic acid. In someembodiments, the said at least one acidulant is citric acid. In someembodiments, the said at least one acidulant is betaine hydrochloride.

In any of the embodiments described herein, the at least one acidulantis an organic acidulant. In some embodiments, the at least one acidulantis selected from tartaric acid, maleic acid, fumaric acid, citric acid,and betaine hydrochloride. In some embodiments, the least one acidulantis fumaric acid. In some embodiments, the at least one acidulant istartaric acid. In some embodiments, the said at least one acidulant ismaleic acid. In some embodiments, the said at least one acidulant iscitric acid. In some embodiments, the said at least one acidulant isbetaine hydrochloride.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant. In some embodiments, the at least oneacidulant is an organic acidulant. In some embodiments, the at least oneacidulant is selected from tartaric acid, maleic acid, fumaric acid,citric acid, and betaine hydrochloride. In some embodiments, the leastone acidulant is fumaric acid. In some embodiments, the at least oneacidulant is tartaric acid. In some embodiments, the said at least oneacidulant is maleic acid. In some embodiments, the said at least oneacidulant is citric acid. In some embodiments, the said at least oneacidulant is betaine hydrochloride.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein the molar ratio between saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand said at least one acidulant is from about 0.5 to about 2.

In some embodiments are provided pharmaceutical compositions in the formof a tablet or capsule. In some embodiments are provided pharmaceuticalcompositions in the form of a tablet. In some embodiments are providedpharmaceutical compositions in the form of a capsule.

In some embodiments are provided pharmaceutical compositions, whereinsaid pharmaceutical composition comprises from about 10 mg to about 1000mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein less than about 2% of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidedegrades in said pharmaceutical composition after said pharmaceuticalcomposition is stored for 3 months in an open container at 40° C. and75% relative humidity.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least acidulant, wherein more than about 98% of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideis present in said pharmaceutical composition after said pharmaceuticalcomposition is stored for 3 months in an open container at 40° C. and75% relative humidity.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein less than about 2% of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidedegrades in said pharmaceutical composition after said pharmaceuticalcomposition is stored for 3 months in an open container at 60° C. and75% relative humidity.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said compositions arenon-hygroscopic.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one pharmaceutically acceptable excipient, wherein saidpharmaceutical composition is in the form of a tablet or capsule, andwherein said tablet or capsule has a dissolution profile wherein atleast about 30% of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidehas been released from said tablet or capsule at about 60 minutes whentested in USP Apparatus Type I Basket Method at 50 rpm in 500 mL ofsodium acetate buffer at a pH of 4.5 and at about 37° C. In someembodiments are provided such pharmaceutical formulations wherein atleast about 40%, or about 50%, or about 60%, or about 70%, or about 80%,or about 90%, or about 95% of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidehas been released from said tablet or capsule at about 60 minutes whentested in USP Apparatus Type I Basket Method at 50 rpm in 500 mL ofsodium acetate buffer at a pH of 4.5 and at about 37° C.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide,wherein said wherein said tablet or capsule has a dissolution profilewherein at least about 20% of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidehas been released from said tablet or capsule at about 45 minutes whentested in USP Apparatus Type I Basket Method at 50 rpm in 500 mL ofsodium acetate buffer at a pH of 4.5 and at about 37° C.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide,wherein said wherein said tablet or capsule has a dissolution profilewherein at least about 15% of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidehas been released from said tablet or capsule at about 30 minutes whentested in USP Apparatus Type I Basket Method at 50 rpm in 500 mL ofsodium acetate buffer at a pH of 4.5 and at about 37° C.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state provides a pharmacokineticprofile in said subject wherein the T_(max) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 2 hours and 6 hoursfollowing said administration of said pharmaceutical composition to saidsubject.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state at a total dose of about 800mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the C_(max)of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 2080 nM and about 2110 nMfollowing said administration of said pharmaceutical composition to saidsubject.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fed state at a total dose of about 800 mgof saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the C_(max)of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between 80% to 125% of 2560 nM, basedon a 90 percent confidence interval following said administration ofsaid pharmaceutical composition to said subject.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state at a total dose of about 800mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the AUC(0 to24) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 28,900 nM*hr and about30,800 nM*hr following said administration of said pharmaceuticalcomposition to said subject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering a C_(max) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 2080 nM and about 2100 nMfollowing administration of said pharmaceutical composition to saidsubject in a fasted state, and wherein said composition comprises atotal dose of about 800 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(0 to 24) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 28,900 nM*hr and about30,800 nM*hr following administration of said pharmaceutical compositionto said subject in a fasted state, and wherein said compositioncomprises a total dose of about 800 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering a T_(max) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 2 hours and about 6 hoursfollowing administration of said pharmaceutical composition to saidsubject in a fasted state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideto a subject that exhibits no food effect.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideto a subject that exhibits no significant food effect.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide,wherein said pharmaceutical composition exhibits no food effect whenadministered to a subject.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide,wherein said pharmaceutical composition exhibits no food effect whenadministered to a subject and said subject is also administered one ormore proton pump inhibitor compounds.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state at a total dose of about 600mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the T_(max)of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 2 hours and about 5 hoursfollowing said administration of said pharmaceutical composition to saidsubject. In some embodiments, the at least one acidulant is an organicacidulant. In some embodiments, the at least one acidulant is selectedfrom tartaric acid, maleic acid, fumaric acid, citric acid, and betainehydrochloride. In some embodiments, the least one acidulant is fumaricacid. In some embodiments, the at least one acidulant is tartaric acid.In some embodiments, the said at least one acidulant is maleic acid. Insome embodiments, the said at least one acidulant is citric acid. Insome embodiments, the said at least one acidulant is betainehydrochloride.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject at a total dose of about 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the T_(max)of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 2 hours and about 8 hoursfollowing said administration of said pharmaceutical composition to saidsubject. In some embodiments, the at least one acidulant is an organicacidulant. In some embodiments, the at least one acidulant is selectedfrom tartaric acid, maleic acid, fumaric acid, citric acid, and betainehydrochloride. In some embodiments, the least one acidulant is fumaricacid. In some embodiments, the at least one acidulant is tartaric acid.In some embodiments, the said at least one acidulant is maleic acid. Insome embodiments, the said at least one acidulant is citric acid. Insome embodiments, the said at least one acidulant is betainehydrochloride.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fed state at a total dose of about 600 mgof saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the T_(max)of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 4 hours and about 8 hoursfollowing said administration of said pharmaceutical composition to saidsubject. In some embodiments, the at least one acidulant is an organicacidulant. In some embodiments, the at least one acidulant is selectedfrom tartaric acid, maleic acid, fumaric acid, citric acid, and betainehydrochloride. In some embodiments, the least one acidulant is fumaricacid. In some embodiments, the at least one acidulant is tartaric acid.In some embodiments, the said at least one acidulant is maleic acid. Insome embodiments, the said at least one acidulant is citric acid. Insome embodiments, the said at least one acidulant is betainehydrochloride.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject at a total dose of about 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the T_(max)of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 4 hours and about 8 hoursfollowing said administration of said pharmaceutical composition to saidsubject. In some embodiments, the at least one acidulant is an organicacidulant. In some embodiments, the at least one acidulant is selectedfrom tartaric acid, maleic acid, fumaric acid, citric acid, and betainehydrochloride. In some embodiments, the least one acidulant is fumaricacid. In some embodiments, the at least one acidulant is tartaric acid.In some embodiments, the said at least one acidulant is maleic acid. Insome embodiments, the said at least one acidulant is citric acid. Insome embodiments, the said at least one acidulant is betainehydrochloride.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state at a total dose of about 600mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the C_(max)of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 1200 nM and about 3500nM, following said administration of said pharmaceutical composition tosaid subject. In some embodiments, the at least one acidulant is anorganic acidulant. In some embodiments, the at least one acidulant isselected from tartaric acid, maleic acid, fumaric acid, citric acid, andbetaine hydrochloride. In some embodiments, the least one acidulant isfumaric acid. In some embodiments, the at least one acidulant istartaric acid. In some embodiments, the said at least one acidulant ismaleic acid. In some embodiments, the said at least one acidulant iscitric acid. In some embodiments, the said at least one acidulant isbetaine hydrochloride.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject at a total dose of about 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the C_(max)of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 1200 nM and about 3500nM, following said administration of said pharmaceutical composition tosaid subject. In some embodiments, the at least one acidulant is anorganic acidulant. In some embodiments, the at least one acidulant isselected from tartaric acid, maleic acid, fumaric acid, citric acid, andbetaine hydrochloride. In some embodiments, the least one acidulant isfumaric acid. In some embodiments, the at least one acidulant istartaric acid. In some embodiments, the said at least one acidulant ismaleic acid. In some embodiments, the said at least one acidulant iscitric acid. In some embodiments, the said at least one acidulant isbetaine hydrochloride.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fed state at a total dose of about 600 mgof saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the C_(max)of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 1500 nM and about 3500 nMfollowing said administration of said pharmaceutical composition to saidsubject. In some embodiments, the at least one acidulant is an organicacidulant. In some embodiments, the at least one acidulant is selectedfrom tartaric acid, maleic acid, fumaric acid, citric acid, and betainehydrochloride. In some embodiments, the least one acidulant is fumaricacid. In some embodiments, the at least one acidulant is tartaric acid.In some embodiments, the said at least one acidulant is maleic acid. Insome embodiments, the said at least one acidulant is citric acid. Insome embodiments, the said at least one acidulant is betainehydrochloride.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject at a total dose of about 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the C_(max)of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 1500 nM and about 3500 nMfollowing said administration of said pharmaceutical composition to saidsubject. In some embodiments, the at least one acidulant is an organicacidulant. In some embodiments, the at least one acidulant is selectedfrom tartaric acid, maleic acid, fumaric acid, citric acid, and betainehydrochloride. In some embodiments, the least one acidulant is fumaricacid. In some embodiments, the at least one acidulant is tartaric acid.In some embodiments, the said at least one acidulant is maleic acid. Insome embodiments, the said at least one acidulant is citric acid. Insome embodiments, the said at least one acidulant is betainehydrochloride.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state at a total dose of about 600mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the AUC(0 to120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 30,000 nM*hr and about85,000 nM*hr following said administration of said pharmaceuticalcomposition to said subject. In some embodiments, the at least oneacidulant is an organic acidulant. In some embodiments, the at least oneacidulant is selected from tartaric acid, maleic acid, fumaric acid,citric acid, and betaine hydrochloride. In some embodiments, the leastone acidulant is fumaric acid. In some embodiments, the at least oneacidulant is tartaric acid. In some embodiments, the said at least oneacidulant is maleic acid. In some embodiments, the said at least oneacidulant is citric acid. In some embodiments, the said at least oneacidulant is betaine hydrochloride.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject state at a total dose of about 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the AUC(0 to120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 30,000 nM*hr and about85,000 nM*hr following said administration of said pharmaceuticalcomposition to said subject. In some embodiments, the at least oneacidulant is an organic acidulant. In some embodiments, the at least oneacidulant is selected from tartaric acid, maleic acid, fumaric acid,citric acid, and betaine hydrochloride. In some embodiments, the leastone acidulant is fumaric acid. In some embodiments, the at least oneacidulant is tartaric acid. In some embodiments, the said at least oneacidulant is maleic acid. In some embodiments, the said at least oneacidulant is citric acid. In some embodiments, the said at least oneacidulant is betaine hydrochloride.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fed state at a total dose of about 600 mgof saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the AUC(0 to120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 35,000 nM*hr and about90,000 nM*hr following said administration of said pharmaceuticalcomposition to said subject. In some embodiments, the at least oneacidulant is an organic acidulant. In some embodiments, the at least oneacidulant is selected from tartaric acid, maleic acid, fumaric acid,citric acid, and betaine hydrochloride. In some embodiments, the leastone acidulant is fumaric acid. In some embodiments, the at least oneacidulant is tartaric acid. In some embodiments, the said at least oneacidulant is maleic acid. In some embodiments, the said at least oneacidulant is citric acid. In some embodiments, the said at least oneacidulant is betaine hydrochloride.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject at a total dose of about 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the AUC(0 to120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 35,000 nM*hr and about90,000 nM*hr following said administration of said pharmaceuticalcomposition to said subject. In some embodiments, the at least oneacidulant is an organic acidulant. In some embodiments, the at least oneacidulant is selected from tartaric acid, maleic acid, fumaric acid,citric acid, and betaine hydrochloride. In some embodiments, the leastone acidulant is fumaric acid. In some embodiments, the at least oneacidulant is tartaric acid. In some embodiments, the said at least oneacidulant is maleic acid. In some embodiments, the said at least oneacidulant is citric acid. In some embodiments, the said at least oneacidulant is betaine hydrochloride.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state at a total dose of about 600mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein theAUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 30,000 nM*hr and about85,000 nM*hr following said administration of said pharmaceuticalcomposition to said subject. In some embodiments, the at least oneacidulant is an organic acidulant. In some embodiments, the at least oneacidulant is selected from tartaric acid, maleic acid, fumaric acid,citric acid, and betaine hydrochloride. In some embodiments, the leastone acidulant is fumaric acid. In some embodiments, the at least oneacidulant is tartaric acid. In some embodiments, the said at least oneacidulant is maleic acid. In some embodiments, the said at least oneacidulant is citric acid. In some embodiments, the said at least oneacidulant is betaine hydrochloride.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject at a total dose of about 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein theAUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 30,000 nM*hr and about85,000 nM*hr following said administration of said pharmaceuticalcomposition to said subject. In some embodiments, the at least oneacidulant is an organic acidulant. In some embodiments, the at least oneacidulant is selected from tartaric acid, maleic acid, fumaric acid,citric acid, and betaine hydrochloride. In some embodiments, the leastone acidulant is fumaric acid. In some embodiments, the at least oneacidulant is tartaric acid. In some embodiments, the said at least oneacidulant is maleic acid. In some embodiments, the said at least oneacidulant is citric acid. In some embodiments, the said at least oneacidulant is betaine hydrochloride.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fed state at a total dose of about 600 mgof saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein theAUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 35,000 nM*hr and about90,000 nM*hr following said administration of said pharmaceuticalcomposition to said subject. In some embodiments, the at least oneacidulant is an organic acidulant. In some embodiments, the at least oneacidulant is selected from tartaric acid, maleic acid, fumaric acid,citric acid, and betaine hydrochloride. In some embodiments, the leastone acidulant is fumaric acid. In some embodiments, the at least oneacidulant is tartaric acid. In some embodiments, the said at least oneacidulant is maleic acid. In some embodiments, the said at least oneacidulant is citric acid. In some embodiments, the said at least oneacidulant is betaine hydrochloride.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject at a total dose of about 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein theAUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 35,000 nM*hr and about90,000 nM*hr following said administration of said pharmaceuticalcomposition to said subject. In some embodiments, the at least oneacidulant is an organic acidulant. In some embodiments, the at least oneacidulant is selected from tartaric acid, maleic acid, fumaric acid,citric acid, and betaine hydrochloride. In some embodiments, the leastone acidulant is fumaric acid. In some embodiments, the at least oneacidulant is tartaric acid. In some embodiments, the said at least oneacidulant is maleic acid. In some embodiments, the said at least oneacidulant is citric acid. In some embodiments, the said at least oneacidulant is betaine hydrochloride.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering a C_(max) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 1200 nM and about 3500 nMfollowing administration of said pharmaceutical composition to saidsubject in a fasted state, and wherein said composition comprises atotal dose of about 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering a C_(max) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 1200 nM and about 3500 nMfollowing administration of said pharmaceutical composition to saidsubject, and wherein said composition comprises a total dose of about600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering a C_(max) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 1500 nM and about 3500 nMfollowing administration of said pharmaceutical composition to saidsubject in a fed state, and wherein said composition comprises a totaldose of about 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering a C_(max) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 1500 nM and about 3500 nMfollowing administration of said pharmaceutical composition to saidsubject, and wherein said composition comprises a total dose of about600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(0 to 120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 30,000 nM*hr and about85,000 nM*hr following administration of said pharmaceutical compositionto said subject in a fasted state, and wherein said compositioncomprises a total dose of about 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(0 to 120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 30,000 nM*hr and about85,000 nM*hr following administration of said pharmaceutical compositionto said subject, and wherein said composition comprises a total dose ofabout 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(0 to 120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 35,000 nM*hr and about90,000 nM*hr following administration of said pharmaceutical compositionto said subject in a fed state, and wherein said composition comprises atotal dose of about 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(0 to 120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 35,000 nM*hr and about90,000 nM*hr following administration of said pharmaceutical compositionto said subject, and wherein said composition comprises a total dose ofabout 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 30,000 nM*hr and about85,000 nM*hr following administration of said pharmaceutical compositionto said subject in a fasted state, and wherein said compositioncomprises a total dose of about 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 30,000 nM*hr and about85,000 nM*hr following administration of said pharmaceutical compositionto said subject, and wherein said composition comprises a total dose ofabout 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 35,000 nM*hr and about90,000 nM*hr following administration of said pharmaceutical compositionto said subject in a fed state, and wherein said composition comprises atotal dose of about 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 35,000 nM*hr and about90,000 nM*hr following administration of said pharmaceutical compositionto said subject, and wherein said composition comprises a total dose ofabout 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering a T_(max) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 2 hours and about 5 hoursfollowing administration of said pharmaceutical composition to saidsubject in a fasted state, and wherein said composition comprises atotal dose of about 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering a T_(max) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 2 hours and about 5 hoursfollowing administration of said pharmaceutical composition to saidsubject, and wherein said composition comprises a total dose of about600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering a T_(max) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 4 hours and about 8 hoursfollowing administration of said pharmaceutical composition to saidsubject in a fed state, and wherein said composition comprises a totaldose of about 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering a T_(max) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 4 hours and about 8 hoursfollowing administration of said pharmaceutical composition to saidsubject, and wherein said composition comprises a total dose of about600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a graphical illustration of the bioavailability (area underthe curve, AUC) ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide,measured in nM*hr/mL, after administration of the F2A formulation underfasted conditions, with and without a PPI.

FIG. 2 is a graphical illustration of the effect of food onbioavailability (area under the curve, AUC) ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide,measured in nM*hr/mL. The F2A formulation was administered under fed orfasted conditions without a PPI.

FIG. 3 is a graphical illustration of the effect of food onbioavailability (area under the curve, AUC) ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide,measured in nM*hr/mL. The F2A formulation was administered under fed orfasted conditions with a PPI.

FIG. 4 is a graphical illustration of the mean plasma levels (innanomolar) over time ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideafter treatment with F2A. Diamonds (♦) indicate administration of F2Aunder fasting conditions without a PPI. Squares (▪) indicateadministration of F2A under fasted conditions with a PPI. Triangles (▴)indicate administration of F2A under fed conditions without a PPI.Circles (∘) indicate administration of F2A under fed conditions with aPPI.

DETAILED DESCRIPTION

The singular form “a,” “an,” and “the” include plural references unlessthe context clearly dictates otherwise. For example, the term “a cell”includes one or more cells, including mixtures thereof. “A and/or B” isused herein to include all of the following alternatives: “A,” “B,” “Aor B,” and “A and B.”

As used herein, the term“N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide”means a compound having Chemical Abstracts Service Registry No.1108743-60-7 and having the chemical structure:

Hereinafter all references toN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideherein include references to solvates, complexes, polymorphic forms,stereoisomers, and isotopically labeled versions thereof. Also includedwithin the scope provided herein are pharmaceutical compositionscomprising solvates, complexes, polymorphic forms, stereoisomers, andisotopically labeled versions ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

As used herein, the term “about” means either within plus or minus 10%of the provided value, or rounded to the nearest significant figure, inall cases inclusive of the provided value. Where ranges are provided,they are inclusive of the boundary values.

As used herein, the term “acidulant” means a chemical compound that isacidic in nature. As used herein, the term “organic acidulant” means anacidulant the chemical composition of which contains carbon. As usedherein, the term “inorganic acidulant” means an acidulant thecomposition of which does not contain carbon.

As used herein, the terms “administration” and “administering” mean thedelivery of a bioactive composition or formulation to a subject by anadministration route including, but not limited to, oral, intravenous,intra-arterial, intramuscular, intraperitoneal, subcutaneous,intramuscular, topically, or combinations thereof. In some embodiments,the administration to a subject is oral.

As used herein, the term “admixture” means a mixture of one or morechemical compounds in a composition. It is understood by one havingordinary skill in the art that the pharmaceutical compositions disclosedherein comprise an admixture ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand the at least one acidulant.

As used herein, the term “ALK” means anaplastic lymphoma kinase receptoror CD246 (cluster of differentiation 246), which is an enzyme that inhumans is encoded by the ALK gene and also has the UniProt identifiedALK_HUMAN.

As used herein, the term “antibody” means an immunoglobulin thatspecifically binds to, and is thereby defined as complementary with, aparticular spatial and polar organization of another molecule. Theantibody can be monoclonal or polyclonal and can be prepared bytechniques that are well known in the art, such as immunization of ahost and collection of sera (polyclonal), or by preparing continuoushybrid cell lines and collecting the secreted protein (monoclonal), orby cloning and expressing nucleotide sequences or mutagenized versionsthereof coding at least for the amino acid sequences required forspecific binding of natural antibodies. Antibodies may include acomplete immunoglobulin or fragment thereof, which immunoglobulinsinclude the various classes and isotypes, such as IgA, IgD, IgE, IgG1,IgG2a, IgG2b and IgG3, IgM, etc. Fragments thereof may include Fab, Fvand F(ab′)2, Fab′, and the like. In addition, aggregates, polymers, andconjugates of immunoglobulins or their fragments can be used whereappropriate so long as binding affinity for a particular target ismaintained.

As used herein, the term “AUC” means the area under the curve of a plotof the concentration of a compound in the plasma of a subject versustime.

As used herein, the term “betaine hydrochloride” means a compound havingChemical Abstracts Service Registry No. 590-46-5 and the common names1-carboxy-n,n,n-trimethylmethanaminium chloride and(carboxymethyl)trimethylammonium hydrochloride.

As used herein, the term “biological sample,” means a sample obtainedfrom an organism that may be used in a diagnostic or monitoring assay.The sample may be of a healthy tissue, diseased tissue or tissuesuspected of being diseased tissue. The sample may be a biopsy taken,for example, during a surgical procedure. The sample may be collectedvia means of fine needle aspiration, scraping or washing a cavity tocollects cells or tissue therefrom. The sample may be of a tumor suchas, for example, solid and hematopoietic tumors as well as ofneighboring healthy tissue. The sample may be a smear of subject cellsor a tissue section. The term encompasses blood and other liquid samplesof biological origin, solid tissue samples, such as a biopsy specimen ortissue cultures or cells derived therefrom and the progeny thereof. Theterm encompasses samples that have been manipulated in any way aftertheir procurement, such as by treatment with reagents, solubilization,or enrichment for certain components. The term encompasses clinicalsamples, and also includes cells in cell culture, cell supernatants,cell lysates, cell extracts, cell homogenates, and subcellularcomponents including synthesized proteins, serum, plasma, bodily andother biological fluids, and tissue samples. The biological sample cancontain compounds that are not naturally intermixed with the cell ortissue in nature such as preservatives, anticoagulants, buffers,fixatives, nutrients, antibiotics or the like. In some embodiments, thesample is preserved as a frozen sample or as formaldehyde- orparaformaldehyde-fixed paraffin-embedded (FFPE) tissue preparation. Forexample, the sample can be embedded in a matrix, e.g., an FFPE block ora frozen sample.

As used herein, the term “biomarker” means one or more compounds whoselevel of nucleic acid or protein product has a quantitativelydifferential concentration or level with respect to an aspect of abiological state of a subject. The term “biomarker” may be used hereininterchangeably with the term “marker.” The level of the biomarker canbe measured at both the nucleic acid level as well as the polypeptidelevel. At the nucleic acid level, a nucleic acid gene or a transcriptwhich is transcribed from any part of the subject's chromosomal andextrachromosomal genome, including for example the mitochondrial genome,may be measured. Preferably an RNA transcript, more preferably an RNAtranscript includes a primary transcript, a spliced transcript, analternatively spliced transcript, or an mRNA of the biomarker ismeasured. At the polypeptide level, a pre-propeptide, a propeptide, amature peptide or a secreted peptide of the biomarker may be measured. Abiomarker can be used either solely or in conjunction with one or moreother identified biomarkers so as to allow correlation to the biologicalstate of interest as defined herein. Specific examples of biomarkerscovered by the present disclosure include those associated with ALK,ROS1, TrkA, TrkB, and TrkC.

As used herein, the term “C_(max)” means the peak concentration that acompound achieves in the plasma of a subject after the compound, or apharmaceutical composition comprising the compound, has beenadministrated to the subject. In some embodiments, the compound, or apharmaceutical composition comprising the compound, is administeredorally to a subject to achieve a particular C_(max).

As used herein, the terms “cancer” or “tumor” may be usedinterchangeably. These terms mean the presence of cells possessingcharacteristics typical of cancer-causing cells, such as uncontrolledproliferation, immortality, metastatic potential, rapid growth andproliferation rate, and certain characteristic morphological features.Cancer cells are often in the form of a tumor, but such cells can existalone within an animal, or can be a non-tumorigenic cancer cell, such asa leukemia cell. These terms include a solid tumor, a soft tissue tumor,or a metastatic lesion. As used herein, the term “cancer” includespremalignant, as well as malignant cancers. In certain embodiments, thecancer is a solid tumor, a soft tissue tumor, or a metastatic lesion.The terms also refer to solid tumors named for the type of cells thatform them, cancer of blood, bone marrow, or the lymphatic system.Examples of solid tumors include, but are not limited to, sarcomas andcarcinomas. Examples of cancers of the blood include, but are notlimited to, leukemias, lymphomas and myeloma. The terms include, but arenot limited to, a primary cancer that originates at a specific site inthe body, a metastatic cancer that has spread from the place in which itstarted to other parts of the body, a recurrence from the originalprimary cancer after remission, and a second primary cancer that is anew primary cancer in a person with a history of previous cancer ofdifferent type from latter one. As used herein “cancer” refers to anymalignant and/or invasive growth or tumor caused by abnormal cellgrowth.

As used herein, the term “chemotherapeutic agent”, means a chemicalsubstance, such as a cytotoxic or cytostatic agent, that is used totreat a condition, particularly cancer.

As used herein, the terms “combination” and “in combination with” meanthe administration ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidetogether with at least one additional pharmaceutical or medicinal agent(e.g., an anti-cancer agent), either sequentially or simultaneously. Itincludes dosing simultaneously, or within minutes or hours of eachother, or on the same day, or on alternating days, or dosing thepharmaceutical compositions provided herein on a daily basis, ormultiple days per week, or weekly basis, for example, whileadministering another compound such as a chemotherapeutic agent on thesame day or alternating days or weeks or on a periodic basis during atime simultaneous therewith or concurrent therewith, or at least a partof the time during which the pharmaceutical compositions disclosedherein is dosed. For example, a pharmaceutical composition as providedherein that comprisesN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidecould be dosed every day or several days a week while thechemotherapeutic agent is dosed on alternating days or alternating weeksor other periods of time, such as every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14 or more days.

As used herein, the term “contact” when used in reference to specificityor specific binding means two molecules are close enough so that shortrange non-covalent chemical interactions, such as Van der Waal forces,hydrogen bonding, hydrophobic interactions, and the like, dominate theinteraction of the molecule.

As used herein, the term “cell line” means to one or more generations ofcells which are derived from a clonal cell. The term “clone,” or “clonalcell,” means a single cell which is expanded to produce an isolatedpopulation of phenotypically similar cells (i.e. a “clonal cellpopulation”).

As used herein, the parameters Dv10, Dv50, Dv90 and Dv99 represent theparticle size at the 10%, 50%, 90% and 99% points of the cumulativevolume undersize particle size distribution. Thus, a “Dv10” for amaterial represents a particle size wherein 10% of the volume of thematerial consists of particles having a particle size equal to the Dv10value or smaller. A “Dv50” for a material represents a particle sizewherein 50% of the volume of the material consists of particles having aparticle size equal to the Dv50 value or smaller. A “Dv90” for amaterial represents a particle size wherein 90% of the volume of thematerial consists of particles having a particle size equal to the Dv90value or smaller. A “Dv99” for a material represents a particle sizewherein 99% of the volume of the material consists of particles having aparticle size equal to the Dv99 value or smaller.

As used herein, the term “food effect” means a change in the rate and/orextent of absorption of a compound in a subject when the compound isadministered to the subject shortly after a meal (fed conditions) ascompared to the rate and/or extent of absorption of the compound whenthe compound is administered to the subject under fasting conditions. Asused herein, the term “no food effect” means that there is nosignificant difference in the rate and/or extent of absorption of acompound in a subject when the compound is administered to the subjectin fed conditions compared to fasting conditions.

As used herein, the term “immunohistochemistry,” means the process oflocalizing antigens (e.g. proteins) in biological samples, cells and/orcells of a tissue section exploiting the principle of antibodies bindingspecifically to antigens. Immunohistochemical staining is widely used inthe diagnosis of abnormal cells such as those found in cancerous tumors.Specific molecular markers are characteristic of particular cellularevents, such as cell proliferation or cell death. Visualizing anantibody-antigen interaction can be accomplished in a number of ways. Inthe most common instance, an antibody is conjugated to an enzyme, suchas peroxidase, that can catalyze a color-producing reaction.Alternatively, the antibody can also be tagged to a fluorophore thusemploying the principles of immunofluorescence. Immunohistochemistry canalso be used to evaluate tumor content in the sample on which qPCR iscarried out in order to account for the fact that qPCR result will beinfluenced by the amount of tumor tissue present.

As used herein, the term “micronization” refers to a process of reducingthe average particle size of a solid material, typically to provideparticles with a particle size of a few micrometers.

As used herein, the term “micronized” means a material that has beensubjected to micronization

As used herein, the terms “monoclonal antibody,” “mAb” and “MAB” mean anantibody that is an immunoglobulin produced by a single clone oflymphocytes which recognizes only a single epitope on an antigen. Forexample, a monoclonal antibody useful for the methods provided hereindisplays a single binding specificity and affinity for a particularepitope of one or more tyrosine kinases.

As used herein, the term “multiplexed assay” means an assay in whichmultiple assay reactions, e.g. simultaneous assays of multiple targetbiomarkers, are carried out in a single reaction chamber and/or andanalyzed in a single separation and detection format.

As used herein, the term “multiplex identification” means thesimultaneous identification of one or more target biomarkers in a singlemixture. For example, a two-plex assay means the simultaneousidentification, in a single reaction mixture, of two different targetbiomarkers.

As used herein, the term “one or more molecular alterations” means anyvariation in the genetic or protein sequence in one or more cells of asubject as compared to the corresponding wild-type genes or proteins.One or more molecular alterations include, but are not limited to,genetic mutations, gene amplifications, splice variants, deletions,insertions/deletions, gene rearrangements, single-nucleotide variations(SNVs), insertions, and aberrant RNA/protein expression.

As used herein, the term “particle size distribution” means the relativeproportions of particles of a compound having a given particle size.While the particle size of a spherical object can be unambiguously andquantitatively defined by its diameter, particles comprising an activepharmaceutical ingredient or an excipient may be non-spherical andirregular in shape. There are several methods by which those of ordinaryskill in the art measure and express the size of non-spherical andirregular particles, such as measuring the size of such particles usinglaser diffractometry and expressing the size of such particles based onreplacing a given particle with an imaginary sphere that has one of anumber of properties of the particle. Such properties can be selectedfrom, for example, but are not limited to, the diameter of an imaginarysphere having the same volume of the particle being measured(volume-based particle size), the diameter of an imaginary sphere havingthe same weight as the particle being measured (weight-based particlesize), and the diameter of an imaginary sphere having the same surfacearea as the particle being measured (area-based particle size). Thosehaving ordinary skill in the art are familiar with such methods, and themanner in which the results of such methods are expressed, and suchmethods can be applied to the embodiments disclosed herein without undueexperimentation. The particle size distribution may be represented, forexample, graphically as a plot. A common type of plot is a cumulativeundersize plot which represents the fraction (e.g. by number, volume ormass) of particles that are smaller than the stated particle size.

As used herein, the term “polyclonal antibody” means a composition ofdifferent antibody molecules which is capable of binding to or reactingwith several different specific antigenic determinants on the same or ondifferent antigens. The variability in antigen specificity of apolyclonal antibody is located in the variable regions of the subjectantibodies constituting the polyclonal antibody, in particular in thecomplementarity determining regions (CDRs). Preferably, the polyclonalantibody is prepared by immunization of an animal with the targettyrosine kinases or portions thereof. Alternatively, the polyclonalantibody may be prepared by mixing multiple monoclonal antibodies havingdesired specificity to a target tyrosine kinase.

As used herein, the term “proton pump inhibitor” or “PPI” refers to adrug that reduces gastric acid production. PPIs that may be used in someembodiments includes herein are, but are not limited to,dexlansoprazole, esomeprazole, ilaprazole, lansoprazole, omeprazole,pantoprazol, picoprazole, rabeprazole, yenatoprazole, and timoprazole.

As used herein, “ROS1” means the ROS1 receptor tyrosine-protein kinasehaving the UniProt designation ROS1 HUMAN.

As used herein, the term “selectively binds” means the situation inwhich one member of a specific intra- or inter-species binding pair willnot show any significant binding to molecules other than its specificintra- or inter-species binding partner (e.g., an affinity of about100-fold less), which means that only minimal cross-reactivity occurs.

As used herein in reference to the binding of two molecules or one ormore compounds and a complex of molecules, the term “specific” means thespecific recognition of one for the other and the formation of a stablecomplex, as compared to substantially less recognition of othermolecules and the lack of formation of stable complexes with such othermolecules. Preferably, “specific,” in reference to binding, means thatto the extent that one or more compounds forms complexes with othermolecules or complexes, it forms at least fifty percent of the complexeswith the molecule or complex for which it has specificity. Generally,the molecules or complexes have areas on their surfaces or in cavitiesgiving rise to specific recognition between the two binding moieties.Exemplary of specific binding are antibody-antigen interactions,enzyme-substrate interactions, polynucleotide hybridizations and/orformation of duplexes, cellular receptor-ligand interactions, and soforth.

As used herein, the term “subject” means a mammal, including, but notlimited to, a human, a dog or a cat. In some embodiments, the subject isa human. In some embodiments, the subject is a dog. In some embodiments,the subject is a cat.

As used herein, the term “T_(max)” means the time when the peakconcentration of a compound in the plasma of a subject is reached afteradministration of the compound, or a pharmaceutical compositioncomprising the compound, to the subject.

As used herein, the term “therapeutically effective amount” means thatamount of the compound or compounds, or pharmaceutically acceptablesalts thereof, being administered to a subject which will relieve tosome extent one or more of the symptoms of the disorder being treated.In reference to the treatment of a cancer, a therapeutically effectiveamount means that amount which has the effect of (1) reducing the sizeof a cancer tumor, (2) inhibiting (that is, slowing to some extent,preferably stopping) cancer tumor metastasis, (3) inhibiting to someextent (that is, slowing to some extent, preferably stopping) cancertumor growth, and/or, (4) relieving to some extent (or, preferably,eliminating) one or more symptoms associated with the cancer.

As used herein, the terms “tropomyosin receptor kinase,” “Trks” and“Trk” mean the family of tropomyosin receptor kinases (Trks) that areactivated by peptide hormones of the neurotrophin family and include,but are not limited to, TrkA, TrkB, and TrkC. As used herein, the term“TrkA” means wild-type tropomyosin receptor kinase A having the UniProtidentifier NTRK1_HUMAN. As used herein, the term “TrkB” means wild-typetropomyosin receptor kinase B having the UniProt identifier NTRK2_HUMAN.As used herein, the term “TrkC” means wild-type tropomyosin receptorkinase C having the UniProt identifier NTRK3_HUMAN. TrkA, TrkB and TrkCare also referred to by those having ordinary skill in the art as Trk1,Trk2 and Trk3, respectively. A reference to TrkA is a reference to Trk1.A reference to TrkB is a reference to Trk2. A reference to TrkC is areference to Trk3

As used herein, the term “USP Apparatus Type I” means the Apparatus 1(Basket Apparatus or Basket Method) and the procedures for using theapparatus that are described in United States Pharmacopeia (USP) GeneralChapter <711>.

As used herein, the term “USP Apparatus Type II” means the Apparatus 2(Paddle Apparatus or Paddle Method) and the procedures for using theapparatus described in United States Pharmacopeia (USP) General Chapter<711>.

In one aspect are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide,at least one acidulant and at least one pharmaceutically acceptableexcipient.

In one aspect are provided pharmaceutical compositions comprising anadmixture ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide,at least one acidulant and at least one pharmaceutically acceptableexcipient.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide,at least one acidulant and at least one pharmaceutically acceptableexcipient. Among the acidulants that may be used in the pharmaceuticalcompositions disclosed herein are organic and inorganic acidulants. Insome embodiments, the at least one acidulant is an organic acidulant. Insome embodiments, the at least one acidulant is an inorganic acidulant.In some embodiments, the at least one organic acidulant is selected fromorganic carboxylic acids, aminium, and iminium salts.

In some embodiments, the acidulant is selected from acetic acid,ascorbic acid, benzoic acid, benzosulfonic acid, betaine hydrochloride,carbonic acid, cinnamic acid, citric acid, ethanesulfonic acid,ethylenediaminetetraacetic acid, dodecylsulfonic acid, fumaric acid,glucoronic acid, glutamic acid, glycolic acid, lactic acid, lactobionicacid, (D) or (L) malic acid or a mixture thereof, maleic acid, mandelicacid, malonic acid, methanesulfonic acid, mucic acid,naphthalenesulfonic acid, propionic acid, salicylic acid, stearic acid,succinic acid, p-toluenesulfonic acid, trifluoroacetic acid, (D) or (L)tartaric acid or a mixture thereof, valeric acid, and the like.

In some embodiments, the at least one acidulant is selected from aceticacid, benzoic acid, betaine hydrochloride, citric acid, fumaric acid,glucoronic acid, lactic acid, (D) or (L) malic acid or a mixturethereof, maleic acid, mandelic acid, malonic acid, salicylic acid,stearic acid, succinic acid, p-toluenesulfonic acid, and (D) or (L)tartaric acid or a mixture thereof.

In some embodiments, the at least one acidulant is selected from benzoicacid, betaine hydrochloride, citric acid, fumaric acid, (D) or (L)maleic acid or a mixture thereof, and (D) or (L) tartaric acid or amixture thereof.

In some embodiments, the at least one acidulant is selected from betainehydrochloride, citric acid, fumaric acid, maleic acid, and (D) or (L)tartaric acid or a mixture thereof.

In some embodiments, the at least one acidulant is betainehydrochloride. In some embodiments, the at least one acidulant is citricacid. In some embodiments, the at least one acidulant is fumaric acid.In some embodiments, the at least one acidulant is maleic acid. In someembodiments, the at least one acidulant is (D) or (L) tartaric acid or amixture thereof.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein the at least one acidulant is(D)-tartaric acid. In some embodiments are provided pharmaceuticalcompositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein the at least one acidulant is(L)-tartaric acid.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition isprepared using wet granulation.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition isprepared using dry granulation. In some embodiments, inclusion of atleast one acidulant in the dry granulation step of drug productmanufacturing creates a low pH micro environment that enhances thesolubility ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition isprepared using wet granulation and the at least one acidulant isselected from tartaric acid, maleic acid, fumaric acid, citric acid, andbetaine hydrochloride. In some embodiments, the least one acidulant isfumaric acid. In some embodiments, the at least one acidulant istartaric acid. In some embodiments, the said at least one acidulant ismaleic acid. In some embodiments, the said at least one acidulant iscitric acid. In some embodiments, the said at least one acidulant isbetaine hydrochloride. In some embodiments, the at least one acidulantis (D) or (L) tartaric acid or a mixture thereof. In some embodiments,the at least one acidulant is (D) tartaric acid. In some embodiments,the at least one acidulant is (L) tartaric acid. In some embodiments,the at least one acidulate is a mixture of (D) and (L) tartaric acid.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition isprepared using dry granulation and the at least one acidulant isselected from tartaric acid, maleic acid, fumaric acid, citric acid, andbetaine hydrochloride. In some embodiments, the least one acidulant isfumaric acid. In some embodiments, the at least one acidulant istartaric acid. In some embodiments, the said at least one acidulant ismaleic acid. In some embodiments, the said at least one acidulant iscitric acid. In some embodiments, the said at least one acidulant isbetaine hydrochloride. In some embodiments, the at least one acidulantis (D) or (L) tartaric acid or a mixture thereof. In some embodiments,the at least one acidulant is (D) tartaric acid. In some embodiments,the at least one acidulant is (L) tartaric acid. In some embodiments,the at least one acidulate is a mixture of (D) and (L) tartaric acid.

In some embodiments, the at least one acidulant has a melting point ofgreater than or equal to about 15° C. In some embodiments, the at leastone acidulant has a melting point of greater than or equal to about 20°C. In some embodiments, the at least one acidulant has a melting pointof greater than or equal to about 25° C. In some embodiments, the atleast one acidulant has a melting point of greater than or equal toabout 30° C. In some embodiments, the at least one acidulant has amelting point of greater than or equal to about 40° C. In someembodiments, the at least one acidulant has a melting point of greaterthan or equal to about 50° C. In some embodiments, the at least oneacidulant has a melting point of greater than or equal to about 75° C.In some embodiments, the at least one acidulant has a melting point ofgreater than or equal to about 100° C. In some embodiments, the at leastone acidulant has a melting point of greater than or equal to about 150°C. In some embodiments, the at least one acidulant has a melting pointof greater than or equal to about 200° C. In some embodiments, the atleast one acidulant has a melting point of greater than or equal toabout 250° C. In some embodiments, the at least one acidulant has amelting point of greater than or equal to about 300° C.

In some embodiments, the at least one acidulant has a pKa of less thanabout 9, or less than about 8, or less than about 7, or less than about6, or less than about 5, or less than about 4, or less than about 3, orless than about 2.

In some embodiments, the at least one acidulant has a pKa of from about1 to about 9, or from about 1 to about 8, or from about 1 to about 7, orfrom about 1 to about 6, or from about 1 to about 5, or from about 1 toabout 4, or from about 1 to about 3.5, or from about 1 to about 3.25, orfrom about 1 to about 3, or from about 1 to about 2.75, or from about 1to about 2.5, or from about 1 to about 2.25, or from about 1 to about 2,or from about 1 to about 1.9, or from about 1.5 to about 5, or fromabout 1.5 to about 4.5, or from about 1.5 to about 4, or from about 1.5to about 3.5, or from about 1.5 to about 3.25, or from about 1.8 toabout 3.5.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant wherein the molar ratio between saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand said at least one acidulant is from about 0.5 to about 2, or fromabout 0.75 to about 1.75, or from about 1 to about 1.75, or from about 1to about 1.5, or from about 1.25 to about 1.75, or from about 1 to about1.5.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant wherein the molar ratio between saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand said at least one acidulant is about 2, or about 1.75, or about 1.5,or about 1.25, or about 1, or about 0.75, or about 0.5. In someembodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant wherein the molar ratio between saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand said at least one acidulant is about 1.5.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said at least one acidulant is (D)tartaric acid, (L) tartaric acid, or a mixture of (D) and (L) tartaricacid, and further wherein the molar ratio between saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand said at least one acidulant is about 2, or about 1.75, or about 1.5,or about 1.25, or about 1, or about 0.75, or about 0.5. In someembodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said at least one acidulant is (D)tartaric acid, (L) tartaric acid, or a mixture of (D) and (L) tartaricacid, and further wherein the molar ratio between saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand said at least one acidulant is about 1.5.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein the molar ratio between saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand said at least one acidulant is from about 0.5 to about 5, or fromabout 0.5 to about 4.5, or from about 0.5 to about 4, or from about 0.5to about 3.5, or from about 0.5 to about 3, or from about 0.5 to about2.75, or from about 0.5 to about 2.5, or from about 0.5 to about 2.25.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand betaine hydrochloride, wherein the molar ratio between saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand said betaine hydrochloride is from about 0.5 to about 5, or fromabout 0.5 to about 4.5, or from about 0.5 to about 4, or from about 0.5to about 3.5, or from about 0.5 to about 3, or from about 0.5 to about2.75, or from about 0.5 to about 2.5, or from about 0.5 to about 2.25.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand betaine hydrochloride, wherein the molar ratio between saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand said betaine hydrochloride is about 0.5. In some embodiments areprovided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand betaine hydrochloride, wherein the molar ratio between saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand said betaine hydrochloride is about 1. In some embodiments areprovided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand betaine hydrochloride, wherein the molar ratio between saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand said betaine hydrochloride is about 1.5. In some embodiments areprovided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand betaine hydrochloride, wherein the molar ratio between saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand said betaine hydrochloride is about 2. In some embodiments areprovided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand betaine hydrochloride, wherein the molar ratio between saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand said betaine hydrochloride is about 2.25. In some embodiments areprovided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand betaine hydrochloride, wherein the molar ratio between saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand said betaine hydrochloride is about 2.5. In some embodiments areprovided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand betaine hydrochloride, wherein the molar ratio between saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand said betaine hydrochloride is about 2.75. In some embodiments areprovided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand betaine hydrochloride, wherein the molar ratio between saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand said betaine hydrochloride is about 3. In some embodiments areprovided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand betaine hydrochloride, wherein the molar ratio between saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand said betaine hydrochloride is about 3.5. In some embodiments areprovided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand betaine hydrochloride, wherein the molar ratio between saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand said betaine hydrochloride is about 4. In some embodiments areprovided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand betaine hydrochloride, wherein the molar ratio between saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand said betaine hydrochloride is about 4.5. In some embodiments areprovided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand betaine hydrochloride, wherein the molar ratio between saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand said betaine hydrochloride is about 5.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant. In some embodiments, the formulationscomprise from about 10 mg to about 1000 mg, or from about 25 mg to about1000 mg, or from about 50 mg to about 1000 mg, or from about 100 mg toabout 1000 mg, or from about 100 mg to about 800 mg, or from about 100mg to about 750 mg, or from about 100 mg to about 500 mg, or from about100 mg to about 300 mg, or from about 100 mg to about 250 mg, or fromabout 100 mg to about 200 mg, or from about 100 mg to 150 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise about 25 mg, or about 50mg, or about 75 mg, or about 100 mg, or about 125 mg, or about 150 mg,or about 175 mg, or about 200 mg, or about 225 mg, or about 250 mg, orabout 275 mg, or about 300 mg, or about 325 mg, or about 350 mg, orabout 375 mg, or about 400 mg, or about 475 mg, or about 500 mg, orabout 525 mg, or about 550 mg, or about 575 mg, or about 600 mg, orabout 625 mg, or about 650 mg, or about 700 mg, or about 750 mg, orabout 800 mg, or about 850 mg, or about 900 mg, or about 950 mg, orabout 1000 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise about 25 mg, or about 50mg, or about 75 mg, or about 100 mg, or about 125 mg, or about 150 mg,or about 175 mg, or about 200 mg, or about 225 mg, or about 250 mg, orabout 275 mg, or about 300 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise about 25 mg, or about 50mg, or about 75 mg, or about 100 mg, or about 125 mg, or about 150 mg,or about 175 mg, or about 200 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise about 100 mg, or about125 mg, or about 150 mg, or about 175 mg, or about 200 mg, or about 225mg, or about 250 mg, or about 275 mg, or about 300 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise about 150 mg, or about175 mg, or about 200 mg, or about 225 mg, or about 250 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise about 100 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise about 150 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise about 200 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise about 250 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise about 300 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise about 350 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise about 400 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise about 450 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise about 500 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

The embodiments of the pharmaceutical compositions provided herein arein a form suitable for oral administration, such as a tablet, capsule,powder, granule, sustained release formulations, solution suspension,suspension or emulsion. In some embodiments, the pharmaceuticalcompositions are in the form of a tablet or capsule. In someembodiments, the pharmaceutical compositions are in the form of atablet. In some embodiments, the tablet is a multi-layer tablet. In someembodiments, the tablet is a multi-layer tablet wherein one or morelayers comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideare separate from one or more layers comprising the at least oneacidulant. In some embodiments, the tablet is a bi-layer tablet whereina layer comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideis separate from a layer comprising the at least one acidulant. In someembodiments any of the multi-layer tablets described herein furthercomprise at least one pharmaceutically acceptable excipient.

In some embodiments, the pharmaceutical compositions are in the form ofa tablet, wherein said tablet comprisesN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant. In some embodiments, the pharmaceuticalcompositions are in the form of a tablet, wherein said tablet comprisesan admixture ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant. In some embodiments any of the tabletsdescribed herein further comprise at least one pharmaceuticallyacceptable excipient.

In some embodiments, the pharmaceutical compositions are in the form ofa tablet, wherein said tablet comprisesN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide,at least one acidulant, and at least one filler. In another embodiment,the tablets further comprise at least one disintegrant. In anotherembodiment, the tablets further comprise at least one glidant. Inanother embodiment, the tablets further comprise at least one lubricant.In another embodiment, the tablets further comprise at least onepore-forming agent. In another embodiment, the tablets further compriseat least one binder. In another embodiment, the tablets further compriseat least one gel-forming agent.

In some embodiments, the pharmaceutical compositions are in the form ofa tablet, wherein said tablet comprisesN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide,and at least one acidulant. In some embodiments, the at least oneacidulant is selected from acetic acid, benzoic acid, betainehydrochloride, citric acid, fumaric acid, glucoronic acid, lactic acid,(D) or (L) malic acid or a mixture thereof, maleic acid, mandelic acid,malonic acid, salicylic acid, stearic acid, succinic acid,p-toluenesulfonic acid, and (D) or (L) tartaric acid or a mixturethereof. In some embodiments, the at least one acidulant is selectedfrom benzoic acid, betaine hydrochloride, citric acid, fumaric acid, (D)or (L) maleic acid or a mixture thereof, and (D) or (L) tartaric acid ora mixture thereof. In some embodiments, the at least one acidulant isselected from betaine hydrochloride, citric acid, fumaric acid, maleicacid, and (D) or (L) tartaric acid or a mixture thereof. In someembodiments, the at least one acidulant is betaine hydrochloride. Insome embodiments, the at least one acidulant is citric acid. In someembodiments, the at least one acidulant is fumaric acid. In someembodiments, the at least one acidulant is maleic acid. In someembodiments, the at least one acidulant is (D) or (L) tartaric acid or amixture thereof.

In some embodiments, the pharmaceutical compositions are in the form ofa tablet, wherein said tablet comprisesN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide,at least one acidulant, and magnesium stearate. In some embodiments theat least one acidulant is selected from acetic acid, benzoic acid,betaine hydrochloride, citric acid, fumaric acid, glucoronic acid,lactic acid, (D) or (L) malic acid or a mixture thereof, maleic acid,mandelic acid, malonic acid, salicylic acid, stearic acid, succinicacid, p-toluenesulfonic acid, and (D) or (L) tartaric acid or a mixturethereof. In some embodiments, the at least one acidulant is selectedfrom benzoic acid, betaine hydrochloride, citric acid, fumaric acid, (D)or (L) maleic acid or a mixture thereof, and (D) or (L) tartaric acid ora mixture thereof. In some embodiments, the at least one acidulant isselected from betaine hydrochloride, citric acid, fumaric acid, maleicacid, and (D) or (L) tartaric acid or a mixture thereof. In someembodiments, the at least one acidulant is betaine hydrochloride. Insome embodiments, the at least one acidulant is citric acid. In someembodiments, the at least one acidulant is fumaric acid. In someembodiments, the at least one acidulant is maleic acid. In someembodiments, the at least one acidulant is (D) or (L) tartaric acid or amixture thereof.

In some embodiments, the pharmaceutical compositions are in the form ofa capsule. In some embodiments, the capsule is a multi-layer capsule. Insome embodiments, the capsule is a multi-layer capsule wherein one ormore layers comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideare separate from one or more layers comprising the at least oneacidulant. In some embodiments, the capsule is a bi-layer capsulewherein a layer comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideis separate from a layer comprising the at least one acidulant. In someembodiments any of the multi-layer capsules described herein furthercomprise at least one pharmaceutically acceptable excipient.

In some embodiments, the pharmaceutical compositions are in the form ofa capsule, wherein said capsule comprises, consists of, or consistsessentially of intragranular components and extragranular componentswithin the capsule. In some embodiments, the intragranular componentscompriseN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant. In some embodiments, the intragranularcomponents further comprise a filler, a binder, a disintegrant, or alubricant, or any combination of two or more thereof. In someembodiments, the intragranular components further comprise lactose,hypromellose, crospovidone, or magnesium stearate, or any combination oftwo or more thereof. In some embodiments, the extragranular componentscomprise a filler, a disintegrant, a glidant, or a lubricant, or anycombination of two or more thereof. In some embodiments, theextragranular components comprise microcrystalline cellulose,crospovidone, colloidal silicon dioxide, or magnesium stearate, or anycombination of two or more thereof.

In some embodiments, the pharmaceutical compositions are in the form ofa capsule, wherein said capsule comprisesN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant. In some embodiments, the pharmaceuticalcompositions are in the form of a capsule, wherein said capsulecomprises an admixture ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant. In some embodiments any of the capsulesdescribed herein further comprise at least one pharmaceuticallyacceptable excipient.

In some embodiments, the pharmaceutical compositions are in the form ofa capsule, wherein said capsule comprisesN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide,at least one acidulant, and at least one filler. In another embodiment,the capsules further comprise at least one disintegrant. In anotherembodiment, the capsules further comprise at least one glidant. Inanother embodiment, the capsules further comprise at least onelubricant.

In some embodiments, the pharmaceutical compositions are in the form ofa capsule, wherein said capsule comprisesN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide,and at least one acidulant. In some embodiments, the at least oneacidulant is selected from acetic acid, benzoic acid, betainehydrochloride, citric acid, fumaric acid, glucoronic acid, lactic acid,(D) or (L) malic acid or a mixture thereof, maleic acid, mandelic acid,malonic acid, salicylic acid, stearic acid, succinic acid,p-toluenesulfonic acid, and (D) or (L) tartaric acid or a mixturethereof. In some embodiments, the at least one acidulant is selectedfrom benzoic acid, betaine hydrochloride, citric acid, fumaric acid, (D)or (L) maleic acid or a mixture thereof, and (D) or (L) tartaric acid ora mixture thereof. In some embodiments, the at least one acidulant isselected from betaine hydrochloride, citric acid, fumaric acid, maleicacid, and (D) or (L) tartaric acid or a mixture thereof. In someembodiments, the at least acidulant is betaine hydrochloride. In someembodiments, the at least one acidulant is citric acid. In someembodiments, the at least one acidulant is fumaric acid. In someembodiments, the at least one acidulant is maleic acid. In someembodiments, the at least one acidulant is (D) or (L) tartaric acid or amixture thereof.

In some embodiments, the pharmaceutical compositions are in the form ofa capsule, wherein said capsule comprisesN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide,at least one acidulant, and magnesium stearate. In some embodiments theat least one acidulant is selected from acetic acid, benzoic acid,betaine hydrochloride, citric acid, fumaric acid, glucoronic acid,lactic acid, (D) or (L) malic acid or a mixture thereof, maleic acid,mandelic acid, malonic acid, salicylic acid, stearic acid, succinicacid, p-toluenesulfonic acid, and (D) or (L) tartaric acid or a mixturethereof. In some embodiments, the at least one acidulant is selectedfrom benzoic acid, betaine hydrochloride, citric acid, fumaric acid, (D)or (L) maleic acid or a mixture thereof, and (D) or (L) tartaric acid ora mixture thereof. In some embodiments, the at least one acidulant isselected from betaine hydrochloride, citric acid, fumaric acid, maleicacid, and (D) or (L) tartaric acid or a mixture thereof. In someembodiments, at one least acidulant is betaine hydrochloride. In someembodiments, the at least one acidulant is citric acid. In someembodiments, the at least one acidulant is fumaric acid. In someembodiments, the at least one acidulant is maleic acid. In someembodiments, the at least one acidulant is (D) or (L) tartaric acid or amixture thereof.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein an amount of about 10 mg to about 2000 mg, or from about 10 mg toabout 1500 mg, or from about 10 mg to about 1000 mg, or from about 10 mgto about 750 mg, or from about 10 mg to about 500 mg, or from about 25mg to about 500 mg, or from about 50 to about 500 mg, or from about 100mg to about 500 mg. Furthermore, the pharmaceutical compositionsprovided herein may containN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein an amount of about 50 mg, about 100 mg, about 150 mg, about 200 mg,about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, orabout 500 mg. In some embodiments, the pharmaceutical compositionsprovided herein containN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein an amount of about 100 mg to about 200 mg. In some embodiments, thepharmaceutical compositions provided herein containN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein an amount of about 25 mg to about 800 mg.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein an amount from about 0.5 w/w % to about 95 w/w %, or from about 1 w/w% to about 95 w/w %, or from about 1 w/w % to about 75 w/w %, or fromabout 5 w/w % to about 75 w/w %, or from about 10 w/w % to about 75 w/w%, or from about 10 w/w % to about 50 w/w %.

In some embodiments, the pharmaceutical composition further compriseslactose. In some embodiments, the lactose is present in the compositionin an amount of about 15% w/w to about 35% w/w. This includes about 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33,34, and 35% w/v, including increments therein, and ranges between two ofthese values (including endpoints). In some embodiments, the lactose ispresent in the composition in an amount of about 25% w/w to about 30%w/w. In some embodiments, the lactose is anhydrous lactose.

In some embodiments, the pharmaceutical composition further compriseshypromellose (hydroxypropyl methylcellulose). In some embodiments, thehypromellose is present in the composition in an amount of about 1% w/wto about 10% w/w. This includes about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10%w/w, including increments therein, and ranges between two of thesevalues (including endpoints). In some embodiments, the hypromellose ispresent in the composition in an amount of about 3% w/w to about 5% w/w.

In some embodiments, the pharmaceutical composition further comprisesmicrocrystalline cellulose. In some embodiments, the microcrystallinecellulose is present in the composition in an amount of about 1% w/w toabout 5% w/w. This includes about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5,or 5%w/w, including increments therein, and ranges between two of thesevalues (including endpoints). In some embodiments, the microcrystallinecellulose is present in the composition in an amount of about 2% w/w toabout 4% w/w.

In some embodiments, the pharmaceutical composition further comprisescrospovidone. In some embodiments, the crospovidone is present in thecomposition in an amount of about 1% w/w to about 10% w/w. This includesabout 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9,9.5, or 10% w/w, including increments therein, and ranges between two ofthese values (including endpoints). In some embodiments, thecrospovidone is present in the composition in an amount of about 4% w/wto about 7% w/w.

In some embodiments, the pharmaceutical composition further comprisescolloidal silicon dioxide. In some embodiments, the colloidal silicondioxide is present in the composition in an amount of about 0.5% w/w toabout 5% w/w. This includes about 0.05, 0.10, 0.15, 0.20, 0.25, 0.3,0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95,1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5% w/w, including increments therein,and ranges between two of these values (including endpoints). In someembodiments, the colloidal silicon dioxide is present in the compositionin an amount of about 0.1% w/w to about 1% w/w. In some embodiments, thecolloidal silicon dioxide is present in the composition in an amount ofabout 0.1% w/w to about 0.5% w/w.

In some embodiments, the pharmaceutical composition further comprisesmagnesium stearate. In some embodiments, the magnesium stearate ispresent in the composition in an amount of about 0.1% w/w to about 5%w/w. This includes about 0.10, 0.15, 0.20, 0.25, 0.3, 0.35, 0.4, 0.45,0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.5, 2, 2.5,3, 3.5, 4, 4.5, or 5% w/w, including increments therein, and rangesbetween two of these values (including endpoints). In some embodiments,the magnesium stearate is present in the composition in an amount ofabout 0.5% w/w to about 2% w/w.

In some embodiments, the pharmaceutical composition further compriseslactose, hypromellose, crospovidone, microcrystalline cellulose,colloidal silicon dioxide, or magnesium stearate, or any combination oftwo or more thereof. In some embodiments, the lactose is anhydrouslactose.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide,tartaric acid, lactose, hypromellose (hydroxypropyl methylcellulose),crospovidone, and magnesium stearate. In some embodiments, thecompositions comprise from about 10 mg to about 1000 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise from about 25 mg to about1000 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise from about 50 mg to about1000 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise from about 100 mg toabout 1000 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise from about 100 mg toabout 800 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise from about 100 mg toabout 750 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise from about 100 mg toabout 500 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise from about 100 mg toabout 300 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise from about 100 mg toabout 250 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise from about 100 mg toabout 200 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In certain embodiments, the compositions comprise about 25 mg, or about50 mg, or about 75 mg, or about 100 mg, or about 125 mg, or about 150mg, or about 175 mg, or about 200 mg, or about 225 mg, or about 250 mg,or about 275 mg, or about 300 mg, or about 325 mg, or about 350 mg, orabout 375 mg, or about 400 mg, or about 475 mg, or about 500 mg, orabout 525 mg, or about 550 mg, or about 575 mg, or about 600 mg, orabout 625 mg, or about 650 mg, or about 700 mg, or about 750 mg, orabout 800 mg, or about 850 mg, or about 900 mg, or about 950 mg, orabout 1000 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise about 10 mg to about 100mg of tartaric acid. This includes about 10 mg to about 90 mg, about 10mg to about 80 mg, about 10 mg to about 70 mg, about 10 mg to about 60mg, about 20 mg to about 100 mg, about 20 mg to about 90 mg, about 20 mgto about 80 mg, about 20 mg to about 70 mg, about 20 mg to about 60 mg,about 30 mg to about 100 mg, about 30 mg to about 90 mg, about 30 mg toabout 80 mg, about 30 mg to about 70 mg, and about 30 mg to about 60 mg.In some embodiments, tartaric acid is present in the compositions in anamount of 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42,43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60,61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78,79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96,97, 98, 99, or 100 mg, including increments therein, or ranges betweentwo of these values (including endpoints).

In some embodiments are provided pharmaceutical compositions,comprising, consisting of, or consisting essentially ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide,tartaric acid, lactose, hypromellose (hydroxypropyl methylcellulose),microcrystalline cellulose, crospovidone, colloidal silicon dioxide, andmagnesium stearate. In some embodiments, the compositions comprise fromabout 10 mg to about 1000 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise from about 25 mg to about1000 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise from about 50 mg to about1000 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise from about 100 mg toabout 1000 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise from about 100 mg toabout 800 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise from about 100 mg toabout 750 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise from about 100 mg toabout 500 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise from about 100 mg toabout 300 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise from about 100 mg toabout 250 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise from about 100 mg toabout 200 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In certain embodiments, the compositions comprise about 25 mg, or about50 mg, or about 75 mg, or about 100 mg, or about 125 mg, or about 150mg, or about 175 mg, or about 200 mg, or about 225 mg, or about 250 mg,or about 275 mg, or about 300 mg, or about 325 mg, or about 350 mg, orabout 375 mg, or about 400 mg, or about 475 mg, or about 500 mg, orabout 525 mg, or about 550 mg, or about 575 mg, or about 600 mg, orabout 625 mg, or about 650 mg, or about 700 mg, or about 750 mg, orabout 800 mg, or about 850 mg, or about 900 mg, or about 950 mg, orabout 1000 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise about 10 mg to about 100mg of tartaric acid. This includes about 10 mg to about 90 mg, about 10mg to about 80 mg, about 10 mg to about 70 mg, about 10 mg to about 60mg, about 20 mg to about 100 mg, about 20 mg to about 90 mg, about 20 mgto about 80 mg, about 20 mg to about 70 mg, about 20 mg to about 60 mg,about 30 mg to about 100 mg, about 30 mg to about 90 mg, about 30 mg toabout 80 mg, about 30 mg to about 70 mg, and about 30 mg to about 60 mg.In some embodiments, tartaric acid is present in the compositions in anamount of 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42,43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60,61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78,79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96,97, 98, 99, or 100 mg, including increments therein, or ranges betweentwo of these values (including endpoints).

In some embodiments are provided pharmaceutical compositions,comprising, consisting essentially of, or consisting of about 20% w/w toabout 60% w/wN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide,about 5% w/w to about 20% w/w tartaric acid, about 15% w/w to about 35%w/w lactose, about 1% w/w to about 10% w/w hypromellose, about 1% w/w toabout 5% w/w microcrystalline cellulose, about 1% w/w to about 10% w/wcrospovidone, about 0.05% w/w to about 5% w/w colloidal silicon dioxide,and about 0.1% w/w to about 5% w/w magnesium stearate. In someembodiments are provided pharmaceutical compositions, comprising,consisting essentially of, or consisting of about 40% w/w to about 50%w/wN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide,about 10% w/w to about 15% w/w tartaric acid, about 25% w/w to about 30%w/w lactose, about 3% w/w to about 5% w/w hypromellose, about 2% w/w toabout 4% w/w microcrystalline cellulose, about 4% w/w to about 7% w/wcrospovidone, about 0.1% w/w to about 1% w/w colloidal silicon dioxide,and about 0.5% w/w to about 2% w/w magnesium stearate.

In some embodiments, a pharmaceutical compositions comprises, consistsessentially of, or consists ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide,tartaric acid, anhydrous lactose, hypromellose, microcrystallinecellulose, crospovidone, colloidal silicon dioxide, and magnesiumstearate, wherein the composition is prepared in a method comprising,consisting essentially of, or consisting of:

-   -   adding        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        anhydrous lactose; hypromellose; an intragranular portion of        crospovidone; and tartaric acid together and blending to form a        first admixture;    -   sieving the first admixture to form a sieved first admixture;    -   blending the sieved first admixture to form a second admixture;    -   sieving the second admixture to form a sieved second admixture;    -   blending the sieved second admixture to form a third admixture;    -   adding an intragranular portion of magnesium stearate to the        third admixture and blending to form a fourth admixture;    -   compacting and milling the fourth admixture to form a fifth        admixture;    -   adding microcrystalline cellulose, an extragranular portion of        crospovidone, and colloidal silicon dioxide to the fifth        admixture and blending to form a sixth admixture; and    -   adding an extragranular portion of magnesium stearate to the        sixth admixture and blending to form the pharmaceutical        composition.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide,fumaric acid, mannitol, pre-gelatinized starch, colloidal silicondioxide, and magnesium stearate. In some embodiments, the compositionscomprise from about 10 mg to about 1000 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise from about 25 mg to about1000 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise from about 50 mg to about1000 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise from about 100 mg toabout 1000 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise from about 100 mg toabout 800 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise from about 100 mg toabout 750 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise from about 100 mg toabout 500 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise from about 100 mg toabout 300 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise from about 100 mg toabout 250 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise from about 100 mg toabout 200 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In certain embodiments, the compositions comprise about 25 mg, or about50 mg, or about 75 mg, or about 100 mg, or about 125 mg, or about 150mg, or about 175 mg, or about 200 mg, or about 225 mg, or about 250 mg,or about 275 mg, or about 300 mg, or about 325 mg, or about 350 mg, orabout 375 mg, or about 400 mg, or about 475 mg, or about 500 mg, orabout 525 mg, or about 550 mg, or about 575 mg, or about 600 mg, orabout 625 mg, or about 650 mg, or about 700 mg, or about 750 mg, orabout 800 mg, or about 850 mg, or about 900 mg, or about 950 mg, orabout 1000 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide,betaine hydrochloride, isomalt, pre-gelatinized starch, colloidalsilicon dioxide, and magnesium stearate. In some embodiments, thecompositions comprise from about 10 mg to about 1000 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise from about 25 mg to about1000 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise from about 50 mg to about1000 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise from about 100 mg toabout 1000 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise from about 100 mg toabout 800 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise from about 100 mg toabout 750 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise from about 100 mg toabout 500 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise from about 100 mg toabout 300 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise from about 100 mg toabout 250 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the compositions comprise from about 100 mg toabout 200 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In certain embodiments, the compositions comprise about 25 mg, or about50 mg, or about 75 mg, or about 100 mg, or about 125 mg, or about 150mg, or about 175 mg, or about 200 mg, or about 225 mg, or about 250 mg,or about 275 mg, or about 300 mg, or about 325 mg, or about 350 mg, orabout 375 mg, or about 400 mg, or about 475 mg, or about 500 mg, orabout 525 mg, or about 550 mg, or about 575 mg, or about 600 mg, orabout 625 mg, or about 650 mg, or about 700 mg, or about 750 mg, orabout 800 mg, or about 850 mg, or about 900 mg, or about 950 mg, orabout 1000 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein less than about 2% of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidedegrades in said pharmaceutical composition after said pharmaceuticalcomposition is stored for 3 months in an open container at 40° C. and75% relative humidity.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein more than about 98% of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideis present in said pharmaceutical composition after said pharmaceuticalcomposition is stored for 3 months in an open container at 40° C. and75% relative humidity.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein less than about 2% of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidedegrades in said pharmaceutical composition after said pharmaceuticalcomposition is stored for 3 months in an open container at 60° C. and75% relative humidity.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein more than about 98% of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideis present in said pharmaceutical composition after said pharmaceuticalcomposition is stored for 3 months in an open container at 60° C. and75% relative humidity.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one pharmaceutically acceptable excipient, wherein saidpharmaceutical composition is in the form of a tablet or capsule, andwherein said tablet or capsule has a dissolution profile wherein atleast about 30%, or at least about 40%, or at least about 50%, or atleast about 60%, or at least about 70%, or at least about 75%, or atleast about 80%, or at least about 85%, or at least about 90% of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidehas been released from said tablet or capsule at about 60 minutes whentested in USP Apparatus Type I Basket Method at 50 rpm in 500 mL ofsodium acetate buffer at a pH of 4.5 and at about 37° C. In someembodiments, the pharmaceutical composition further comprises at leastone acidulant.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one pharmaceutically acceptable excipient, wherein saidpharmaceutical composition is in the form of a tablet or capsule, andwherein said tablet or capsule has a dissolution profile wherein atleast about 20%, or at least about 30%, or at least about 40%, or atleast about 50%, or at least about 60%, or at least about 70% or atleast about 75% of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidehas been released from said tablet or capsule at about 45 minutes whentested in USP Apparatus Type I Basket Method at 50 rpm in 500 mL ofsodium acetate buffer at a pH of 4.5 and at about 37° C. In someembodiments, the pharmaceutical composition further comprises at leastone acidulant.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one pharmaceutically acceptable excipient, wherein saidpharmaceutical composition is in the form of a tablet or capsule, andwherein said tablet or capsule has a dissolution profile wherein atleast about 15%, or at least about 20%, or at least about 30%, or atleast about 40%, or at least about 50% of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidehas been released from said tablet or capsule at about 30 minutes whentested in USP Apparatus Type I Basket Method at 50 rpm in 500 mL ofsodium acetate buffer at a pH of 4.5 and at about 37° C. In someembodiments, the pharmaceutical composition further comprises at leastone acidulant.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one pharmaceutically acceptable excipient, wherein saidpharmaceutical composition is in the form of a tablet or capsule, andwherein said tablet or capsule has a dissolution profile wherein atleast about 10%, or at least about 15%, or at least about 20% of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidehas been released from said tablet or capsule at about 15 minutes whentested in USP Apparatus Type I Basket Method at 50 rpm in 500 mL ofsodium acetate buffer at a pH of 4.5 and at about 37° C. In someembodiments, the pharmaceutical composition further comprises at leastone acidulant.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide,at least one acidulant, and mannitol or isomalt. In some embodiments areprovided pharmaceutical compositions comprising mannitol. In someembodiments are provided pharmaceutical compositions comprising isomalt.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide,at least one acidulant, mannitol or isomalt, and starch. In someembodiments the weight to weight ratio of said mannitol or isomalt tosaid starch in said pharmaceutical composition is from about 1 to 1 toabout 10 to 1, or from about 1 to 1 to about 7 to 1, or from about 1 to1 to about 6 to 1, or from about 1 to 1 to about 5 to 1, or from about1.5 to 1 to about 3 to 1, or from about 1.75 to 1 to about 3 to 1, orfrom about 1 to 1 to about 2.5 to 1, or from about 1 to 1 to about 2 to1.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide,at least one acidulant, mannitol or isomalt, and starch. In someembodiments the weight to weight ratio of said mannitol or isomalt tosaid starch in said pharmaceutical composition is about 10 to 1, orabout 7 to 1, or about 6 to 1, or about 5 to 1, or about 4 to 1, orabout 3 to 1, or about 2 to 1, or about 1.8 to 1, or about 1.5 to 1, orabout 1 to 1.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide,at least one acidulant and at least one pharmaceutically acceptableexcipient. In some embodiments are provided pharmaceutical compositionswherein said at least one pharmaceutically acceptable excipient isselected from diluents, lubricants, binding agents, disintegratingagents, effervescing mixtures, dyestuffs, sweeteners, and wettingagents.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state provides a pharmacokineticprofile in said subject wherein the Tmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 2 hours and 6 hoursfollowing said administration of said pharmaceutical composition to saidsubject. In some embodiments, the Tmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is about 5 hours following saidadministration of said pharmaceutical composition to said subject.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fed state provides a pharmacokineticprofile in said subject wherein the Tmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 5 hours and 12 hoursfollowing said administration of said pharmaceutical composition to saidsubject. In some embodiments, the Tmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is about 8 hours following saidadministration of said pharmaceutical composition to said subject.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state at a total dose of about 800mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the Cmax ofsaidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 2080 nM and about 2110 nMfollowing said administration of said pharmaceutical composition to saidsubject.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state at a total dose of about 800mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the Cmax ofsaidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 2080 nM and about 2560 nMfollowing said administration of said pharmaceutical composition to saidsubject.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state at a total dose of about 800mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the Cmax ofsaidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between 80% to 125% of 2080 nM, basedon a 90 percent confidence interval following said administration ofsaid pharmaceutical composition to said subject.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fed state at a total dose of about 800 mgof saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the Cmax ofsaidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between 80% to 125% of 2560 nM, basedon a 90 percent confidence interval following said administration ofsaid pharmaceutical composition to said subject.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state at a total dose of about 800mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the AUC(0 to24) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 28,900 nM*hr and about30,800 nM*hr following said administration of said pharmaceuticalcomposition to said subject.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fed state at a total dose of about 800 mgof saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the AUC(0 to24) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is about 40,400 nM*hr following saidadministration of said pharmaceutical composition to said subject.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state at a total dose of about 800mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the AUC(0 to24) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is within about 80% to about 125% of30,800 nM*hr at a 90% confidence interval following said administrationof said pharmaceutical composition to said subject.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fed state at a total dose of about 800 mgof saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the AUC(0 to24) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is within about 80% to about 125% of40,400 nM*hr at a 90% confidence interval following said administrationof said pharmaceutical composition to said subject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering a Cmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 2080 nM and about 2100 nMfollowing administration of said pharmaceutical composition to saidsubject in a fasted state, and wherein said composition comprises atotal dose of about 800 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering a Cmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of about 2560 nM following administration ofsaid pharmaceutical composition to said subject in a fed state, andwherein said composition comprises a total dose of about 800 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(0 to 24) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 28,900 nM*hr and about30,800 nM*hr following administration of said pharmaceutical compositionto said subject in a fasted state, and wherein said compositioncomprises a total dose of about 800 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(0 to 24) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of about 40,400 nM*hr followingadministration of said pharmaceutical composition to said subject in afed state, and wherein said composition comprises a total dose of about800 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering a Tmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 2 hours and about 6 hoursfollowing administration of said pharmaceutical composition to saidsubject in a fasted state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering a Tmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 5 hours and about 12 hoursfollowing administration of said pharmaceutical composition to saidsubject in a fed state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering a Cmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 2080 nM, basedon a 90 percent confidence interval, following administration of saidpharmaceutical composition to said subject in a fasted state, andwherein said composition comprises a total dose of about 800 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering a Cmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 2560 nM, basedon a 90 percent confidence interval, following administration of saidpharmaceutical composition to said subject in a fed state, and whereinsaid composition comprises a total dose of about 800 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(0 to 24) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 30,800 nM*hr,based on a 90 percent confidence interval, following administration ofsaid pharmaceutical composition to said subject in a fasted state, andwherein said composition comprises a total dose of about 800 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(0 to 24) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 40,400 nM*hr,based on a 90 percent confidence interval, following administration ofsaid pharmaceutical composition to said subject in a fed state, andwherein said composition comprises a total dose of about 800 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideto a subject that exhibits no food effect.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide,wherein said pharmaceutical composition exhibits no food effect whenadministered to a subject.

It is understood by those having ordinary skill in the art thatreferences made to “pharmaceutical compositions provided herein,” andthe like, mean those pharmaceutical compositions that are described asembodiments herein. By way of example only, a method of treating asubject having cancer comprising administering to said subject apharmaceutical composition as provided herein, means a method oftreating a subject having cancer comprising administering to saidsubject any of the compositions described herein that compriseN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

In some embodiments are provided pharmaceutical compositions providedherein for use as a medicament. In some embodiments, the medicament isfor use in the treatment of abnormal cell growth in a mammal. In someembodiments, the abnormal cell growth is cancer. In some embodiments,the medicament is for use in the treatment of abnormal cell growthmediated by one or more of ALK, ROS1, TrkA, TrkB and TrkC in a mammal.In some embodiments, the medicament is for use in the treatment ofabnormal cell growth mediated by at least one molecular alteration inone or more of ALK, ROS1, TrkA, TrkB and TrkC in a mammal. In someembodiments, the medicament is for use in the treatment of abnormal cellgrowth mediated by at least one molecular alteration in ALK in a mammal.In some embodiments, the medicament is for use in the treatment ofabnormal cell growth mediated by at least one molecular alteration inROS1 in a mammal. In some embodiments, the medicament is for use in thetreatment of abnormal cell growth mediated by at least one molecularalteration in TrkA in a mammal. In some embodiments, the medicament isfor use in the treatment of abnormal cell growth mediated by at leastone molecular alteration in TrkB in a mammal. In some embodiments, themedicament is for use in the treatment of abnormal cell growth mediatedby at least one molecular alteration in TrkC in a mammal. In some suchembodiments, the molecular alteration is the EML4-ALK fusion protein. Insome embodiments, the molecular alteration is the EML4-ALK fusionprotein having at least one mutation. In some embodiments, the mutationis L1196M. In some embodiments, the mutation is C1156Y.

In some embodiments are provided methods for the treatment of abnormalcell growth in a mammal comprising administering to a mammal atherapeutically effective amount of one or more pharmaceuticalcompositions provided herein. In some embodiments, the abnormal cellgrowth is mediated by at least one molecular alteration in one or moreof ALK, ROS1, TrkA, TrkB and TrkC in a mammal. In some embodiments, theabnormal cell growth is mediated by at least one molecular alteration inALK in a mammal. In some embodiments, the abnormal cell growth ismediated by at least one molecular alteration in ROS1 in a mammal. Insome embodiments, the abnormal cell growth is mediated by at least onemolecular alteration in TrkA in a mammal. In some embodiments, theabnormal cell growth is mediated by at least one molecular alteration inTrkB in a mammal. In some embodiments, the abnormal cell growth ismediated by at least one molecular alteration in TrkC in a mammal. Insome such embodiments, the molecular alteration is the EML4-ALK fusionprotein. In some embodiments, the molecular alteration is the EML4-ALKfusion protein having at least one mutation. In some embodiments, themutation is L1196M. In some embodiments, the mutation is C1156Y.

In some embodiments are provided methods for the treatment of abnormalcell growth in a mammal comprising administering to a mammal an amountof one or more pharmaceutical compositions provided herein, incombination with an amount of an anti-tumor agent, which amounts aretogether effective in treating said abnormal cell growth. In someembodiments, the anti-tumor agent is selected from the group consistingof mitotic inhibitors, alkylating agents, anti-metabolites,intercalating antibiotics, growth factor inhibitors, radiation, cellcycle inhibitors, enzymes, topoisomerase inhibitors, biological responsemodifiers, antibodies, cytotoxics, anti-hormones, and anti-androgens.

In some embodiments are provided one or more pharmaceutical compositionsprovided herein for use in the treatment of abnormal cell growth in amammal. In a further aspect, are disclosed the uses of one or morepharmaceutical compositions described herein for the treatment ofabnormal cell growth in a mammal.

In yet another aspect, are disclosed uses of one or more pharmaceuticalcompositions described herein for the preparation of a medicament forthe treatment of abnormal cell growth.

In frequent embodiments of the methods and uses described herein, theabnormal cell growth is cancer. In some embodiments, the cancer isselected from lung cancer, bone cancer, pancreatic cancer, skin cancer,cancer of the head or neck, cutaneous or intraocular melanoma, uterinecancer, ovarian cancer, rectal cancer, cancer of the anal region,stomach cancer, colon cancer, breast cancer, carcinoma of the fallopiantubes, carcinoma of the endometrium, carcinoma of the cervix, carcinomaof the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of theesophagus, cancer of the small intestine, cancer of the endocrinesystem, cancer of the thyroid gland, cancer of the parathyroid gland,cancer of the adrenal gland, sarcoma of soft tissue, cancer of theurethra, cancer of the penis, prostate cancer, chronic or acuteleukemia, lymphocytic lymphomas, cancer of the bladder, cancer of thekidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis,neoplasms of the central nervous system (CNS), primary CNS lymphoma,spinal axis tumors, brain stem glioma, pituitary adenoma, andcombinations thereof.

In some embodiments, the cancer is selected from the group consisting ofnon-small cell lung cancer (NSCLC), squamous cell carcinoma,hormone-refractory prostate cancer, papillary renal cell carcinoma,colorectal adenocarcinoma, neuroblastomas, anaplastic large celllymphoma (ALCL) and gastric cancer.

In some embodiments, the methods described herein further compriseadministering to the mammal an amount of an anti-cancer therapeuticagent or a palliative agent, which amounts are together effective intreating said abnormal cell growth. In some such embodiments, one ormore anti-cancer therapeutic agent are selected from anti-tumor agents,anti-angiogenesis agents, signal transduction inhibitors andantiproliferative agents, which amounts are together effective intreating said abnormal cell growth.

In other embodiments, the uses described herein comprise the use of oneor more pharmaceutical compositions provided herein in combination withone or more substances selected from anti-tumor agents,anti-angiogenesis agents, signal transduction inhibitors andantiproliferative agents.

In some embodiments, the pharmaceutical compositions described hereinare adapted for use in combination with one or more substances selectedfrom anti-tumor agents, anti-angiogenesis agents, signal transductioninhibitors and antiproliferative agents.

Each of the embodiments of the pharmaceutical compositions providedherein can be combined with one or more other embodiments of thepharmaceutical compositions described herein that is not inconsistentwith the embodiment(s) with which it is combined.

In addition, each of the embodiments provided herein envisions withinits scope that the pharmaceutical compositions described may compriseN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide,or a pharmaceutically acceptable salt ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide.

In some embodiments are provided methods for treating diseases caused byand/or associated with deregulated protein kinase activity, particularlyPLK family, protein kinase C in different isoforms, Met, PAK-4, PAK-5,ZC-1, STLK-2, DDR-2, Aurora 1, Aurora 2, Bub-1, Chk1, Chk2, HER2, raf1,MEK1, MAPK, EGF-R, PDGF-R, FGF-R, FLT3, JAK2, IGF-R, ALK, PI3K, weelkinase, Src, Abl, Akt, MAPK, ILK, MK-2, IKK-2, Cdc7, Nek, Cdk/cyclinkinase family, more particularly Aurora 2, IGF-1R and ALK activity, andROS1 activity, and further more particularly ALK activity and/or ROS1activity, which comprises administering to a mammal in need thereof aneffective amount of one or more pharmaceutical compositions providedherein.

In some embodiments are provided methods to treat a disease caused byand/or associated with dysregulated protein kinase activity selectedfrom the group consisting of cancer and cell proliferative disorders.

In some embodiments are provided methods to treat specific types ofcancer comprising carcinoma, squamous cell carcinoma, hematopoietictumors of myeloid or lymphoid lineage, tumors of mesenchymal origin,tumors of the central and peripheral nervous system, melanoma, seminoma,teratocarcinoma, osteosarcoma, xeroderma pigmentosum, angiosarcoma,glioblastoma, holangiocarcinoma, inflammatory myofibroblastic tumor,epitheloid hemangioendothelioma, astrocytoma, meningioma, angiosarcoma,epitheloid hemangiothelioma, keratocanthomas, thyroid follicular cancer,Kaposi's sarcoma, and pancreatic cancer.

In some embodiments are provided methods to treat specific types ofcancer such as, but not restricted to, breast cancer, lung cancer,colorectal cancer, prostate cancer, ovarian cancer, endometrial cancer,gastric cancer, clear cell renal cell carcinoma, invasive ductalcarcinoma (breast), uveal melanoma, multiple myeloma, rhabdomyosarcoma,Ewing's sarcoma, Kaposi's sarcoma, pancreatic cancer, neuroblastoma, andmedulloblastoma.

In some embodiments are provided methods to treat ALK+ anaplastic largecell lymphomas (ALCL) and possibly other indications in which the ALKactivity might play a role, like neuroblastoma, rhabdomyosarcoma,glioblastoma, inflammatory myofibroblastic tumor, and some kind ofmelanomas, breast carcinomas, Ewings sarcomas, retinoblastomas andnon-small cell lung carcinomas (NSCLC).

In some embodiments are provided methods to treat, reduce the symptomsof, ameliorate the symptoms of, delay the onset of, or otherwisepharmaceutically address pancreatic cancer and possibly otherindications in which a defect in the modulation of ROS1 activity, orupregulation, misregulation or deletion thereof might play a role byadministering one or more pharmaceutical compositions provided herein.

In some embodiments are provided methods to treat, reduce the symptomsof, ameliorate the symptoms of, delay the onset of, or otherwisepharmaceutically address pancreatic cancer and possibly otherindications in which a defect in the modulation of ALK, ROS1, TrkA,TrkB, or TrkC activity, or a combination thereof, or upregulation,misregulation or deletion thereof might play a role by administering oneor more pharmaceutical compositions provided herein.

In some embodiments are provided methods to treat, reduce the symptomsof, ameliorate the symptoms of, delay the onset of, or otherwisepharmaceutically address pancreatic cancer and possibly otherindications in which a defect in the modulation of ROS1 activity, orupregulation, misregulation or deletion thereof might play a role byadministering one or more pharmaceutical compositions provided herein.

In some embodiments are provided methods to treat, reduce the symptomsof, ameliorate the symptoms of, delay the onset of, or otherwisepharmaceutically address pancreatic cancer and possibly otherindications in which a defect in the modulation of ALK, ROS1, TrkA,TrkB, or TrkC activity, or a combination thereof, or upregulation,misregulation or deletion thereof might play a role by administering oneor more pharmaceutical compositions provided herein.

In some embodiments, methods to treat, reduce the symptoms of,ameliorate the symptoms of, delay the onset of, or otherwisepharmaceutically address pancreatic cancer associated with a ROS1down-regulation defect, for example a null mutation such as a ROS1deletion by identifying a ROS1 down-regulation defect, for example anull mutation such as a ROS1 deletion in a cancer or precancerouspancreatic cell in an subject, and administering to the subject one ormore pharmaceutical compositions provided herein.

In some embodiments are provided methods to treat, reduce the symptomsof, ameliorate the symptoms of, delay the onset of, or otherwisepharmaceutically address pancreatic cancer associated with a ALK, ROS1,TrkA, TrkB, or TrkC down-regulation defect, for example a null mutationsuch as a ALK, ROS1, TrkA, TrkB, or TrkC deletion by identifying a ALK,ROS1, TrkA, TrkB, or TrkC down-regulation defect, for example a nullmutation such as a ALK, ROS1, TrkA, TrkB, or TrkC deletion in a canceror precancerous pancreatic cell in an subject, and administering to thesubject one or more pharmaceutical compositions provided herein.

In some embodiments identifying a ROS1 modulation defect such as anupregulation defect or a down-regulation defect, for example a nullmutation such as a ROS1 deletion or a ROS1 chimeric locus encoding aconstitutively active ROS1 kinase in a cancer or precancerous pancreaticcell in an subject comprises assaying for ROS1 activity in a cellextract from a pancreatic cancerous or precancerous cell population.

In some embodiments are provided methods to treat, reduce the symptomsof, ameliorate the symptoms of, delay the onset of, or otherwisepharmaceutically address pancreatic cancer and possibly otherindications in which a defect in the modulation of ALK, ROS1, TrkA,TrkB, or TrkC activity, or a combination thereof, or upregulation,misregulation or deletion thereof might play a role by administering oneor more pharmaceutical compositions provided herein. In some embodimentsare provided methods to treat, reduce the symptoms of, ameliorate thesymptoms of, delay the onset of, or otherwise pharmaceutically addresspancreatic cancer and possibly other indications in which a defect inthe modulation of ROS1, TrkA, TrkB, or TrkC activity, or a combinationthereof, activity, or upregulation, misregulation or deletion thereofmight play a role by administering one or more pharmaceuticalcompositions provided herein.

In some embodiments are provided methods to treat, reduce the symptomsof, ameliorate the symptoms of, delay the onset of, or otherwisepharmaceutically address pancreatic cancer in a subject, and possiblyother indications in such subject in which a defect in the modulation ofROS1, TrkA, TrkB, or TrkC activity, or a combination thereof, activity,or upregulation, misregulation or deletion thereof might play a role byadministering to the subject one or more of the pharmaceuticalcompositions provided herein.

In some embodiments are provided methods to treat, reduce the symptomsof, ameliorate the symptoms of, delay the onset of, or otherwisepharmaceutically address pancreatic cancer in a subject, which cancer isassociated with a ALK, ROS1, TrkA, TrkB, or TrkC down-regulation defect,for example a null mutation such as a ALK, ROS1, TrkA, TrkB, or TrkCdeletion by identifying a ALK, ROS1, TrkA, TrkB, or TrkC down-regulationdefect, for example a null mutation such as a ALK, ROS1, TrkA, TrkB, orTrkC deletion in a cancer or precancerous pancreatic cell in an subject,and administering to the subject one or more pharmaceutical compositionsprovided herein.

In some embodiments are provided methods to treat, reduce the symptomsof, ameliorate the symptoms of, delay the onset of, or otherwisepharmaceutically address a condition in a subject selected fromnon-small cell lung cancer, papillary thyroid cancer, neuroblastoma,pancreatic cancer and colorectal cancer and possibly other indicationsin which a defect in the modulation of ALK, ROS1, TrkA, TrkB, or TrkCactivity, or a combination thereof, or upregulation, misregulation ordeletion thereof might play a role by administering to the subject oneor more of the pharmaceutical compositions provided herein.

In some embodiments are provided methods to treat, reduce the symptomsof, ameliorate the symptoms of, delay the onset of, or otherwisepharmaceutically address a condition in a subject selected fromnon-small cell lung cancer, papillary thyroid cancer, neuroblastoma,pancreatic cancer and colorectal cancer and possibly other indicationsin which a defect in the modulation of ROS1, TrkA, TrkB, or TrkCactivity, or a combination thereof, activity, or upregulation,misregulation or deletion thereof might play a role by administering tothe subject one or more of the pharmaceutical compositions providedherein.

In some embodiments are provided methods to treat, reduce the symptomsof, ameliorate the symptoms of, delay the onset of, or otherwisepharmaceutically address a condition in a subject selected fromnon-small cell lung cancer, papillary thyroid cancer, neuroblastoma,pancreatic cancer and colorectal cancer associated with a ROS1down-regulation defect, for example a null mutation such as a ROS1deletion by identifying a ROS1 down-regulation defect, for example anull mutation such as a ROS1 deletion in a cancer or precancerous cellin an subject, and administering to the subject one or morepharmaceutical compositions provided herein.

In some embodiments are provided methods to treat, reduce the symptomsof, ameliorate the symptoms of, delay the onset of, or otherwisepharmaceutically address a condition in a subject selected fromnon-small cell lung cancer, papillary thyroid cancer, neuroblastoma,pancreatic cancer and colorectal cancer associated with a ALK, ROS1,TrkA, TrkB, or TrkC down-regulation defect, for example a null mutationsuch as a ALK, ROS1, TrkA, TrkB, or TrkC deletion by identifying a ALK,ROS1, TrkA, TrkB, or TrkC down-regulation defect, for example a nullmutation such as a ALK, ROS1, TrkA, TrkB, or TrkC deletion in a canceror precancerous cell in an subject, and administering to the subject oneor more of the pharmaceutical compositions provided herein.

In some embodiments are provided methods to treat cell proliferativedisorders such as, but not restricted to, benign prostate hyperplasia,familial adenomatosis polyposis, neuro-fibromatosis, psoriasis,atherosclerosis and conditions involving vascular smooth muscleproliferation or neointimal formation such as restenosis followingangioplasty or surgery, pulmonary fibrosis, arthritis,glomerulonephritis, retinopathies comprising diabetic and neonatalretinopathies and age related macular degeneration, graft vesseldisease, such as can occur following vessel or organ transplantation,acromegaly and disorders secondary to acromegaly as well as otherhypertrophic conditions in which IGF/IGF-1R signaling is implicated,such as fibrotic lung disease, pathologies related to chronic or acuteoxidative stress or hyperoxia induced tissue damage, and metabolicdisorders in which elevated IGF levels or IGF-1R activity areimplicated, such as obesity.

In some embodiments are provided methods of affecting tumor angiogenesisand metastasis inhibition.

In some embodiments, the methods provided herein further comprisesubjecting the mammal in need thereof to a radiation therapy orchemotherapy regimen in combination with at least one cytostatic orcytotoxic agent. In some embodiments, the methods provided hereinfurther comprise inhibiting the activity ALK protein which comprisescontacting the said protein with an effective amount of one or morepharmaceutical compositions provided herein.

In some embodiments, the methods provided herein for inhibiting at leastone of ALK, ROS1, TrkA, TrkB, or TrkC kinase activity, or a combinationthereof, in a cell, comprising contacting said cell with an effectiveamount of one or more pharmaceutical compositions provided herein.

In some embodiments are provided pharmaceutical compositions comprisingone or more pharmaceutical compositions provided herein and apharmaceutically acceptable excipient, carrier or diluent.

Some embodiments provide methods of inhibiting ALK, ROS1, TrkA, TrkB, orTrkC activity, or a combination thereof, in a subject, comprisingadministering to said subject an effective amount of one or morepharmaceutical compositions provided herein.

Some embodiments provide methods of treating cancer in a subject in needthereof, the method comprising inhibiting ALK, ROS1, TrkA, TrkB, or TrkCactivity, or a combination thereof, in said subject, by administering tosaid subject an effective amount of one or more pharmaceuticalcompositions provided herein.

Some embodiments provide methods of treating non-small cell lung cancer,papillary thyroid cancer, neuroblastoma, pancreatic cancer or colorectalcancer in a subject, comprising administering to said subject aneffective amount of one or more pharmaceutical compositions providedherein.

Some embodiments provide methods of treating tumors in a subject, saidmethods comprising administering to the subject an effective amount ofone or more pharmaceutical compositions provided herein.

Some embodiments provide methods wherein the tumors are caused by thepresence of non-small cell lung cancer, papillary thyroid cancer,neuroblastoma, pancreatic cancer or colorectal cancer in the subject.Some embodiments provide methods wherein one or more of the cellscomprising the tumors in the subject test positive for the presence of agene that expresses at least one of ALK, ROS1, TrkA, TrkB, or TrkCkinase or one or more of the cells comprising the tumors in said subjectdemonstrates at least one of ALK, ROS1, TrkA, TrkB, or TrkC kinaseactivity.

Some embodiments provide methods wherein one or more of the cellscomprising the tumors in the subject test positive for at least one generearrangement comprising the gene, or a fragment thereof, that expressesat least one of ALK, ROS1, TrkA, TrkB, or TrkC kinase. Some embodimentsprovide such methods wherein the cells test positive for at least one ofROS1, TrkA, TrkB, or TrkC kinases. Some embodiments provide methodswherein the cells test positive for ROS1 kinase. Some embodimentsprovide methods wherein the cells test positive for at least one ofTrkA, TrkB and TrkC kinase. Some embodiments provide methods wherein thecells test positive for TrkA kinase. Some embodiments provide methodswherein the cells test positive for TrkB kinase. Some embodimentsprovide such methods wherein the cells test positive for TrkC kinase.

Some embodiments provide methods of treating cancer in a subject, themethod comprising: (1) testing one or more cells comprising the tumorsin the subject for the presence of at least one of ALK, ROS1, TrkA,TrkB, or TrkC kinase; and (2) administering to the subject an effectiveamount of one or more pharmaceutical compositions provided herein.

Some embodiments provide methods of treating cancer in a subject, themethod comprising: (1) testing one or more cells comprising the tumorsin the subject for the presence of at least one molecular alteration inALK, ROS1, TrkA, TrkB, or TrkC kinase; and (2) administering to thesubject an effective amount of one or more pharmaceutical compositionsprovided herein.

Some embodiments provide methods of treating cancer in a subject,wherein one or more cancerous cells in said subject express at least oneof ROS1, TrkA, TrkB, or TrkC kinase, the method comprising administeringto the subject an effective amount of one or more pharmaceuticalcompositions provided herein.

Some embodiments provide a method for treating a subject having cancer,wherein tumors from said subject are ROS1, TrkA, TrkB, or TrkC positive,a combination thereof, the method comprising administering to thesubject an effective amount of one or more pharmaceutical compositionsprovided herein.

Some embodiments provide a method of treating a cancer subject,comprising (a) acquiring knowledge of the presence of at least onegenetic alteration in at least one target gene in the cancer subject,wherein the at least one target gene is selected from ALK1, BDNF, NGF,NGFR, NTF3, NTF4, ROS1, SORT1, NTRK1, NTRK2, and NTRK3; (b) selectingone or more pharmaceutical compositions provided herein as a treatmentfor the cancer subject, based on the recognition that saidpharmaceutical composition is effective in treating cancer subjectshaving said at least one genetic alteration in said at least one targetgene; and (c) administering a therapeutically effective amount of one ormore of said pharmaceutical compositions to said cancer subject.

Some embodiments provide a method of treating a cancer subject,comprising administering to said cancer subject a therapeuticallyeffective amount of one or more pharmaceutical compositions providedherein, wherein prior to said administration of said one or morepharmaceutical compositions said cancer subject is known to possess atleast one genetic alteration in at least one target gene selected fromALK1, BDNF, NGF, NGFR, NTF3, NTF4, ROS1, SORT1, NTRK1, NTRK2, and NTRK3.

Some embodiments provide a method of treating a cancer subject, whereinprior to said treatment said subject is known to possess at least onegenetic alteration in at least one target gene, comprising administeringto said cancer subject a therapeutically effective amount of one or morepharmaceutical compositions provided herein and wherein said at leastone target gene is selected from ALK1, BDNF, NGF, NGFR, NTF3, NTF4,ROS1, SORT1, NTRK1, NTRK2, and NTRK3.

Some embodiments provide any of the methods described herein wherein thesubject or subject is suffering from cancer and the cancer is selectedfrom at least one of non-small cell lung cancer, papillary thyroidcancer, neuroblastoma, pancreatic cancer and colorectal cancer.

In one aspect, provided herein are methods for treating cancer in asubject, comprising (a) acquiring knowledge of the presence of one ormore molecular alterations in a biological sample from the cancersubject, wherein the one or more molecular alterations is detected by anassay comprising one or more antibodies that bind to one or more of ALK,ROS1, TrkA, TrkB, and TrkC biomarkers; (b) selecting a chemotherapeuticagent as a treatment for the cancer subject wherein the assay detectsthe presence of one or more of molecular alterations, and wherein theselected chemotherapeutic agent is one or more of the pharmaceuticalcompositions provided herein, or a pharmaceutically acceptable saltthereof; and (c) administering a therapeutically effective amount of theone or more selected chemotherapeutic agents to the cancer subject.

In another aspect, provided herein are methods for selecting a cancersubject who is predicted to respond to the administration of atherapeutic regimen, comprising (a) acquiring knowledge of the presenceof one or more molecular alterations in a biological sample from thecancer subject, wherein the one or more molecular alterations isdetected by an assay comprising one or more antibodies that bind to oneor more of ALK, ROS1, TrkA, TrkB, and TrkC biomarkers; and (b) selectingthe subject as predicted to respond to the administration of atherapeutic regimen if the one or more molecular alterations is detectedin one or more of the biomarkers, or selecting the subject as predictedto not respond to the administration of a therapeutic regimen if the oneor more molecular alterations is not detected in the biomarkers. In themethods according to this aspect of the disclosure, the therapeuticregiment includes administering to the selected subject atherapeutically effective amount of one or more of the pharmaceuticalcompositions provided herein.

It will be appreciated that the actual dosagesN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidewill vary according the particular composition formulated, the mode ofadministration, and the particular site, subject or subject, and diseasebeing treated. Those skilled in the art using conventionaldosage-determination tests in view of the experimental data forN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidemay ascertain optimal dosages for a given set of conditions. For oraladministration, an exemplary daily dose generally employed will be fromabout 0.001 to about 1000 mg/kg, from about 0.1 mg to about 1000 mg ofbody weight, with courses of treatment repeated at appropriateintervals.

This amount will vary depending upon a variety of factors, comprisingbut not limited to the characteristics of the pharmaceuticalcompositions and formulations provided herein (comprising activity,pharmacokinetics, pharmacodynamics, and bioavailability thereof), thephysiological condition of the subject treated (comprising age, sex,disease type and stage, general physical condition, responsiveness to agiven dosage, and type of medication) or cells, the nature of thepharmaceutically acceptable carrier mg/kg or carriers in theformulation, and the route of administration. Further, an effective ortherapeutically effective amount may vary depending on whether the oneor more pharmaceutical compositions provided herein is administeredalone or in combination with other drug(s), other therapy/therapies orother therapeutic method(s) or modality/modalities. One skilled in theclinical and pharmacological arts will be able to determine an effectiveamount or therapeutically effective amount through routineexperimentation, namely by monitoring a cell's or subject's response toadministration of the one or more pharmaceutical compositions andformulations provided herein and adjusting the dosage accordingly.

In some embodiments, a dose ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidemay range from about 0.1 mg/kg to about 100 mg/kg or more, depending onthe factors mentioned above. In other alternatives, the dosage may rangefrom about 0.1 mg/kg to about 100 mg/kg; or about 1 mg/kg to about 100mg/kg; or about 5 mg/kg up to about 100 mg/kg. For topical applicationssuch as, for example, treatment of various hair conditions, according tosome alternatives provided herein, suitable dosage may range from about1 mg/kg to about 10 g/kg; or about 10 mg/kg to about 1 g/kg; or about 50mg/kg up to about 10 g/kg. Additional guidance with regard to thisaspect can be found in, for example, Remington: The Science and Practiceof Pharmacy, 21st Edition, Univ. of Sciences in Philadelphia (USIP),Lippincott Williams & Wilkins, Philadelphia, Pa., 2005.

Some embodiments include any of the methods described herein, whereinany of the pharmaceutical compositions provided herein that compriseN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideare administered to a subject in an amount such that the amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidethe subject receives ranges from about 200 mg/m² to about 1600 mg/m², orfrom about 200 mg/m² to about 1200 mg/m², or from about 200 mg/m² toabout 1000 mg/m², or from about 400 mg/m² to about 1200 mg/m², or fromabout 400 mg/m² to about 1000 mg/m², or from about 800 mg/m² to about1000 mg/m², or from about 800 mg/m² to about 1200 mg/m², or from about800 mg/m² to about 1200 mg/m², or from about 800 mg/m² to about 1600mg/m².

Some embodiments include any of the methods described herein, whereinany of the pharmaceutical compositions provided herein that compriseN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideare administered to a subject in an amount such that the amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidethe subject receives is about 200 mg/m², about 300 mg/m², about 400mg/m², about 500 mg/m², about 600 mg/m², about 700 mg/m², about 800mg/m², about 900 mg/m², about 1000 mg/m², about 1100 mg/m², about 1200mg/m², about 1300 mg/m², about 1400 mg/m², about 1500 mg/m², about 1600mg/m², about 1700 mg/m², about 1800 mg/m², about 1900 mg/m², or about2000 mg/m². In some embodiments, the amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidethe subject receives is about 200 mg/m², about 300 mg/m², about 400mg/m², about 500 mg/m², about 600 mg/m². In some embodiments, the amountofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidethe subject receives is about 200 mg/m². In some embodiments, the amountofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidethe subject receives is about 300 mg/m². In some embodiments, the amountofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidethe subject receives is about 400 mg/m². In some embodiments, the amountofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidethe subject receives is about 500 mg/m². In some embodiments, the amountofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidethe subject receives is about 600 mg/m².

Some embodiments include any of the methods described herein, whereinany of the pharmaceutical compositions provided herein that compriseN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideare administered to a subject in an amount such that the amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidethe subject receives is about 200 mg, about 300 mg, about 400 mg, about500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg,about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900mg, or about 2000 mg. In some embodiments, the amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidethe subject receives is about 200 mg, about 300 mg, about 400 mg, about500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about1000 mg. In some embodiments, the amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidethe subject receives is about 200 mg. In some embodiments, the amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidethe subject receives is about 300 mg. In some embodiments, the amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidethe subject receives is about 400 mg. In some embodiments, the amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidethe subject receives is about 500 mg. In some embodiments, the amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidethe subject receives is about 600 mg. In some embodiments, the amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidethe subject receives is about 700 mg. In some embodiments, the amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidethe subject receives is about 800 mg. In some embodiments, the amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidethe subject receives is about 900 mg. In some embodiments, the amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidethe subject receives is about 1000 mg.

Some embodiments include any of the methods described herein, whereinany of the pharmaceutical compositions provided herein that compriseN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideare administered to a subject once per day in an amount such that theamount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidethe subject receives per day is about 200 mg, about 300 mg, about 400mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg,about 1900 mg, or about 2000 mg. In some embodiments, the amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidethe subject receives once per day is about 200 mg. In some embodiments,the amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidethe subject receives once per day is about 300 mg. In some embodiments,the amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidethe subject receives once per day is about 400 mg. In some embodiments,the amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidethe subject receives once per day is about 500 mg. In some embodiments,the amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidethe subject receives once per day is about 600 mg. In some embodiments,the amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidethe subject receives once per day is about 700 mg. In some embodiments,the amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidethe subject receives once per day is about 800 mg. In some embodiments,the amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidethe subject receives once per day is about 900 mg. In some embodiments,the amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidethe subject receives once per day is about 1000 mg.

Those of ordinary skill in the art will understand that with respect topharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovided herein the particular pharmaceutical composition, the dosage,and the number of doses given per day to a mammal requiring suchtreatment, are all choices within the knowledge of one of ordinary skillin the art and can be determined without undue experimentation.

Accordingly, while certain dose and administration regimens areexemplified herein, these examples in no way limit the dose andadministration regimen that may be provided to a subject in practicingthe presently disclosed methods.

It is to be noted that dosage values may vary with the type and severityof the condition to be alleviated, and may include single or multipledoses. It is to be further understood that for any particular subject,specific dosage regimens should be adjusted over time according to thesubject need and the professional judgment of the person administeringor supervising the administration of the compositions, and that dosageranges set forth herein are exemplary only and are not intended to limitthe scope or practice of the claimed composition. For example, doses maybe adjusted based on pharmacokinetic or pharmacodynamic parameters,which may include clinical effects such as toxic effects and/orlaboratory values. The embodiments provided herein are intended toencompass intra-subject dose-escalation as determined by the skilledartisan. Determining appropriate dosages and regimens for administrationof the chemotherapeutic agent are well-known in the relevant art andwould be understood to be encompassed by the skilled artisan onceprovided the teachings provided herein.

Implementations of the methods of the present disclosure can include oneor more of the following features. In some embodiments, the selectedchemotherapeutic agent one or more of the pharmaceutical compositionsprovided herein. In some embodiments, the assay includes one or moreantibodies that bind to at least two of ALK, ROS1, TrkA, TrkB and TrkCbiomarkers. In some embodiments, the one or more molecular alterationsdetected in the biological sample involve at least two, at least three,or at least four of the biomarkers. In some embodiments, the knowledgeof the presence of the one or more molecular alterations in thebiological sample is acquired from an assay that includes contacting thebiological sample with one or more antibodies or fragments thereofspecific for the biomarkers. In some embodiments, the specificantibodies are monoclonal antibodies. In some embodiments, the specificantibodies include at least one of D5F3®, D4D5®, C17F1®, andcombinations thereof. In some embodiments, the biological sample iscontacted with one or more of the specific antibodies simultaneously. Insome embodiments, the biological sample is sequentially contacted withthe specific antibodies. In some embodiments, the one or more molecularalterations results in elevated expression of one or more of the ALK,ROS1, TrkA, TrkB, and TrkC biomarkers. In some embodiments, theknowledge of the one or more molecular alterations is acquired from anassay wherein determining whether the expression of one or morebiomarker is elevated includes: (a) determining the expression level ofthe one or more biomarkers in the biological sample; and (b) comparingthe determined expression level to a reference expression level. In someembodiments, the knowledge of the one or more molecular alterations isacquired from an antibody-based assay. In some embodiments, theantibody-based assay is selected from the group consisting of ELISA,immunohistochemistry, western blotting, mass spectrometry, flowcytometry, protein-microarray, immunofluorescence, and a multiplexdetection assay. In some embodiments, the antibody-based assay includesan immunohistochemistry analysis.

In some embodiments, implementations of the methods provided hereinfurther include acquiring knowledge of a genetic alteration in thecancer of the subject from a second analytical assay prior to theadministering step, wherein the second analytical assay is selected fromthe group consisting of capillary electrophoresis, nucleic acidsequencing, polypeptide sequencing, restriction digestion, nucleic acidamplification-based assays, nucleic acid hybridization assay,comparative genomic hybridization, real-time PCR, quantitative reversetranscription PCR (qRT-PCR), PCR-RFLP assay, HPLC, mass-spectrometricgenotyping, fluorescent in-situ hybridization (FISH), next generationsequencing (NGS), and a kinase activity assay. In some embodiments, thecancer is cancer is selected from the group consisting of anaplasticlarge-cell lymphoma (ALCL), colorectal cancer (CRC), cholangiocarcinoma,gastric, glioblastomas (GBM), leiomyosarcoma, melanoma, non-small celllung cancer (NSCLC), squamous cell lung cancer, neuroblastoma (NB),ovarian cancer, pancreatic cancer, prostate cancer, medullary thyroidcancer, breast cancer, and papillary thyroid cancer. In someembodiments, the knowledge of the one or more molecular alterations isobtained from an assay performed simultaneously on a plurality ofbiological samples. In some embodiments, the plurality of biologicalsamples includes at least 6, 12, 24, 48, 96, 200, 384, 400, 500, 1000,1500, or 3000 samples. In some embodiments, the one or more molecularalterations is selected from a genetic mutation, a gene amplification, agene rearrangement, a single-nucleotide variation (SNV), a deletion, aninsertion, an InDel mutation, a single nucleotide point mutation (SNP),an epigenetic alteration, a splicing variant, an RNA/proteinoverexpression, an aberrant RNA/protein expression, and any combinationthereof. In some embodiments, the one or more molecular alterationsinclude an insertion of a heterologous nucleic acid sequence within acoding sequence of a biomarker gene. In some embodiments, the insertionforms a chimeric nucleic acid sequence that encodes a fusion peptide. Insome embodiments, the acquiring knowledge of the one or more molecularalterations further includes determining a nucleic acid sequence and/oran amino acid sequence comprising the one or more molecular alterations.

Some embodiments provide a pharmaceutical composition comprising one ormore pharmaceutical compositions provided herein in combination with oneor more chemotherapeutic agents or radiotherapy, such as radiotherapy ascommonly administered to treat, ameliorate the symptoms of, or preventor delay the onset of cancer. Such agents can include, but are notlimited to, antihormonal agents such as antiestrogens, antiandrogens andaromatase inhibitors, topoisomerase I inhibitors, topoisomerase IIinhibitors, agents that target microtubules, platin-based agents,alkylating agents, DNA damaging or intercalating agents, antineoplasticantimetabolites, other kinase inhibitors, other anti-angiogenic agents,inhibitors of kinesins, therapeutic monoclonal antibodies, inhibitors ofmTOR, histone deacetylase inhibitors, farnesyl transferase inhibitors,and inhibitors of hypoxic response.

Some embodiments provide a product or kit comprising one or morepharmaceutical compositions provided herein and one or morechemotherapeutic agents, as a combined preparation for simultaneous,separate or sequential use in anticancer therapy.

Some embodiments provide one or more pharmaceutical compositions asprovided herein for use as a medicament.

Some embodiments provide the use of one or more pharmaceuticalcompositions as provided herein in the manufacture of a medicament withantitumor activity.

Some embodiments include any of the methods described herein, whereinsaid cancer is selected from non-small cell lung cancer, papillarythyroid cancer, neuroblastoma, pancreatic cancer and colorectal cancer.Some embodiments are any of the methods described herein wherein saidcancer is non-small cell lung cancer. Some embodiments include any ofthe methods described herein, wherein said cancer is said cancer ispapillary thyroid cancer. Some embodiments include any of the methodsdescribed herein, wherein said cancer is wherein said cancer isneuroblastoma. Some embodiments include any of the methods describedherein, wherein said cancer is wherein said cancer is pancreatic cancer.Some embodiments include any of the methods described herein, whereinsaid cancer is wherein said cancer is colorectal cancer.

The pharmaceutically acceptable carrier may comprise a conventionalpharmaceutical carrier or excipient. Suitable pharmaceutical carriersinclude inert diluents or fillers, glidants, lubricants, water andvarious organic solvents (such as hydrates and solvates). Thepharmaceutical compositions may, if desired, contain additionalingredients such as flavorings, binders, excipients and the like. Thusfor oral administration, tablets containing various excipients, such ascitric acid may be employed together with various disintegrants such asstarch, alginic acid and certain complex silicates and with bindingagents such as sucrose, gelatin and acacia. In some embodiments, theexcipient comprises pre-gelatinized starch. In some embodiments, thepharmaceutical compositions comprise a glidant. In some embodiments, thepharmaceutical compositions comprise colloidal silicon dioxide.Additionally, lubricating agents such as magnesium stearate, sodiumlauryl sulfate and talc are often useful for tableting purposes. Solidcompositions of a similar type may also be employed in soft and hardfilled gelatin capsules. Non-limiting examples of materials, therefore,include lactose or milk sugar and high molecular weight polyethyleneglycols.

To treat or prevent diseases or conditions mediated by ALK, ROS1, TrkA,TrkB, or TrkC, or a combination thereof, a pharmaceutical compositionprovided herein is administered by combining a therapeutically effectiveamount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant. Optionally, such pharmaceutical compositionsmay comprise one or more pharmaceutically suitable carriers, which maybe selected, for example, from diluents, excipients and auxiliaries thatfacilitate processing ofN[-5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideinto the final pharmaceutical preparations.

The pharmaceutical carriers employed may be either solid or liquid.Exemplary solid carriers are lactose, sucrose, talc, gelatin, agar,pectin, acacia, magnesium stearate, stearic acid and the like. Exemplaryliquid carriers are syrup, peanut oil, olive oil, water and the like.Similarly, the inventive compositions may include time-delay ortime-release material known in the art, such as glyceryl monostearate orglyceryl distearate alone or with a wax, ethylcellulose,hydroxypropylmethylcellulose, methylmethacrylate or the like. Furtheradditives or excipients may be added to achieve the desired formulationproperties. For example, a bioavailability enhancer, such as Labrasol,Gelucire or the like, or formulator, such as CMC(carboxy-methylcellulose), PG (propyleneglycol), or PEG(polyethyleneglycol), may be added. Gelucire®, a semi-solid vehicle thatprotects active ingredients from light, moisture and oxidation, may beadded, e.g., when preparing a capsule formulation.

If a solid carrier is used, the preparation can be tableted, placed in ahard gelatin capsule in powder or pellet form, or formed into a trocheor lozenge. The amount of solid carrier may vary, but generally will befrom about 25 mg to about 1 g. If a liquid carrier is used, thepreparation may be in the form of syrup, emulsion, soft gelatin capsule,sterile injectable solution or suspension in an ampoule or vial ornon-aqueous liquid suspension. If a semi-solid carrier is used, thepreparation may be in the form of hard and soft gelatin capsuleformulations. The inventive compositions are prepared in unit-dosageform appropriate for the mode of administration, e.g. parenteral or oraladministration.

To obtain a stable water-soluble dose form,N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidemay be dissolved in an aqueous solution of an organic or inorganic acid,such as a 0.3 M solution of succinic acid or citric acid. If a solublesalt form is not available,N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidemay be dissolved in a suitable co-solvent or combinations ofco-solvents. Examples of suitable co-solvents include alcohol, propyleneglycol, polyethylene glycol 300, polysorbate 80, glycerin and the likein concentrations ranging from 0 to 60% of the total volume. In anexemplary embodiment,N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideis dissolved in DMSO and diluted with water. The pharmaceuticalcomposition may also be in the form of a solution of a salt form ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein an appropriate aqueous vehicle such as water or isotonic saline ordextrose solution.

Proper formulation is dependent upon the route of administrationselected. For injection,N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidemay be formulated into aqueous solutions, preferably in physiologicallycompatible buffers such as Hanks solution, Ringer's solution, orphysiological saline buffer. For transmucosal administration, penetrantsappropriate to the barrier to be permeated are used in the formulation.Such penetrants are generally known in the art.

For oral administration,N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidemay be formulated by combining it with pharmaceutically acceptablecarriers known in the art. Such carriers enableN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideto be formulated as tablets, pills, dragees, capsules, powders,granules, liquids, gels, syrups, slurries, suspensions and the like, fororal ingestion by a subject to be treated. Pharmaceutical preparationsfor oral use can be obtained using a solid excipient in admixture withN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide,optionally grinding the resulting mixture, and processing the mixture ofgranules after adding suitable auxiliaries, if desired, to obtaintablets or dragee cores. Suitable excipients include: fillers such assugars, comprising isomalt, lactose, sucrose, mannitol, or sorbitol; andcellulose preparations, for example, maize starch, wheat starch, ricestarch, potato starch, gelatin, gum, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose,microcrystalline cellulose or polyvinylpyrrolidone (PVP). In someembodiments, the filler is mannitol, isomalt, hypromellose(hydroxypropylmethylcellulose), or microcrystalline cellulose. In someembodiments, the filler is mannitol. In some embodiments, the filler isisomalt. In some embodiments, the filler is microcrystalline cellulose.In some embodiments, the filler is lactose. In some embodiments, thefiller is anhydrous lactose. If desired, disintegrating agents may beadded, such as crosslinked polyvinyl pyrrolidone, agar, or alginic acidor a salt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, polyvinyl pyrrolidone, Carbopol gel, polyethylene glycol,and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings.

Pharmaceutical preparations that can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can containN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein admixture with fillers such as lactose, binders such as starches,and/or lubricants such as talc or magnesium stearate, and, optionally,stabilizers. In soft capsules,N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidemay be dissolved or suspended in suitable liquids, such as fatty oils,liquid paraffin, or liquid polyethylene glycols. In addition,stabilizers may be added. All formulations for oral administrationshould be in dosages suitable for such administration.

For buccal administration, the compositions may take the form of tabletsor lozenges formulated in conventional manner.

The pharmaceutical compositions provided herein are useful for thetreatment of cancers comprising but not limited to cancers of the:circulatory system, for example, heart (sarcoma [angiosarcoma,fibrosarcoma, rhabdomyosarcoma, liposarcoma], myxoma, rhabdomyoma,fibroma, lipoma and teratoma), mediastinum and pleura, and otherintrathoracic organs, vascular tumors and tumor-associated vasculartissue; respiratory tract, for example, nasal cavity and middle ear,accessory sinuses, larynx, trachea, bronchus and lung such as small celllung cancer (SCLC), non-small cell lung cancer (NSCLC), bronchogeniccarcinoma (squamous cell, undifferentiated small cell, undifferentiatedlarge cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchialadenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma;gastrointestinal system, for example, esophagus (squamous cellcarcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach(carcinoma, lymphoma, leiomyosarcoma), gastric, pancreas (ductaladenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors,vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors,Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma,fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma,hamartoma, leiomyoma); genitourinary tract, for example, kidney(adenocarcinoma, Wilm's tumor [nephroblastoma], lymphoma, leukemia),bladder and/or urethra (squamous cell carcinoma, transitional cellcarcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis(seminoma, teratoma, embryonal carcinoma, teratocarcinoma,choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma,fibroadenoma, adenomatoid tumors, lipoma); liver, for example, hepatoma(hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma,angiosarcoma, hepatocellular adenoma, hemangioma, pancreatic endocrinetumors (such as pheochromocytoma, insulinoma, vasoactive intestinalpeptide tumor, islet cell tumor and glucagonoma); bone, for example,osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibroushistiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma(reticulum cell sarcoma), multiple myeloma, malignant giant cell tumorchordoma, osteochronfroma (osteocartilaginous exostoses), benignchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma andgiant cell tumors; nervous system, for example, neoplasms of the centralnervous system (CNS), primary CNS lymphoma, skull cancer (osteoma,hemangioma, granuloma, xanthoma, osteitis deformans), meninges(meningioma, meningiosarcoma, gliomatosis), brain cancer (astrocytoma,medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastomamultiform, oligodendroglioma, schwannoma, retinoblastoma, congenitaltumors), spinal cord neurofibroma, meningioma, glioma, sarcoma);reproductive system, for example, gynecological, uterus (endometrialcarcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia),ovaries (ovarian carcinoma [serous cystadenocarcinoma, mucinouscystadenocarcinoma, unclassified carcinoma], granulosa-thecal celltumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma),vulva (squamous cell carcinoma, intraepithelial carcinoma,adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma,squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma),fallopian tubes (carcinoma) and other sites associated with femalegenital organs; placenta, penis, prostate, testis, and other sitesassociated with male genital organs; hematologic system, for example,blood (myeloid leukemia [acute and chronic], acute lymphoblasticleukemia, chronic lymphocytic leukemia, myeloproliferative diseases,multiple myeloma, myelodysplastic syndrome), Hodgkin's disease,non-Hodgkin's lymphoma [malignant lymphoma]; oral cavity, for example,lip, tongue, gum, floor of mouth, palate, and other parts of mouth,parotid gland, and other parts of the salivary glands, tonsil,oropharynx, nasopharynx, pyriform sinus, hypopharynx, and other sites inthe lip, oral cavity and pharynx; skin, for example, malignant melanoma,cutaneous melanoma, basal cell carcinoma, squamous cell carcinoma,Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma,dermatofibroma, and keloids; adrenal glands: neuroblastoma; and othertissues comprising connective and soft tissue, retroperitoneum andperitoneum, eye, intraocular melanoma, and adnexa, breast, head or/andneck, anal region, thyroid, parathyroid, adrenal gland and otherendocrine glands and related structures, secondary and unspecifiedmalignant neoplasm of lymph nodes, secondary malignant neoplasm ofrespiratory and digestive systems and secondary malignant neoplasm ofother sites.

More specifically, examples of cancer when used herein in connectionwith pharmaceutical compositions provided herein include cancer selectedfrom lung cancer (NSCLC and SCLC), cancer of the head or neck, ovariancancer, colon cancer, rectal cancer, prostate cancer, cancer of the analregion, stomach cancer, breast cancer, cancer of the kidney or ureter,renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of thecentral nervous system (CNS), primary CNS lymphoma, non-Hodgkins'slymphoma, spinal axis tumors, or a combination of one or more of theforegoing cancers.

In some embodiments, the pharmaceutical compositions provided herein areuseful for the treatment of cancers, comprising Spitz melanoma,perineural invasion, pulmonary large cell neuroendocrine carcinoma,uterine carcinoma, juvenile breast cancer, nasopharyngeal carcinoma,adenoid cystic cancer, meduallary thyroid cancer, salivary cancer,congenital infantile fibrosarcoma, mesoblastic nephroma, esophagealcancer (squamous), diffuse large B-cell lymphoma, papillary thyroidcancer, and mammary analogue secretory carcinoma.

In some embodiments are provided methods for treating diseases caused byand/or associated with deregulated protein kinase activity, particularlyPLK family, protein kinase C in different isoforms, Met, PAK-4, PAK-5,ZC-1, STLK-2, DDR-2, Aurora 1, Aurora 2, Bub-1, Chk1, Chk2, HER2, raf1,MEK1, MAPK, EGF-R, PDGF-R, FGF-R, FLT3, JAK2, IGF-R, ALK, PI3K, weelkinase, Src, Abl, Akt, MAPK, ILK, MK-2, IKK-2, Cdc7, Nek, Cdk/cyclinkinase family, more particularly Aurora 2, IGF-1R and ALK activity, andROS1 activity, and further more particularly ALK activity and/or ROS1activity, which comprises administering to a mammal in need thereof aneffective amount of a pharmaceutical composition provided herein.

In some embodiments disclosed herein are directed to treat a diseasecaused by and/or associated with dysregulated protein kinase activityselected from the group consisting of cancer and cell proliferativedisorders.

In some embodiments are provided methods to treat specific types ofcancer comprising carcinoma, squamous cell carcinoma, hematopoietictumors of myeloid or lymphoid lineage, tumors of mesenchymal origin,tumors of the central and peripheral nervous system, melanoma, seminoma,teratocarcinoma, osteosarcoma, xeroderma pigmentosum, angiosarcoma,glioblastoma, holangiocarcinoma, inflammatory myofibroblastic tumor,epitheloid hemangioendothelioma, astrocytoma, meningioma, angiosarcoma,epitheloid hemangiothelioma, keratocanthomas, thyroid follicular cancer,Kaposi's sarcoma, and pancreatic cancer.

Some embodiments disclosed herein are directed to treating specifictypes of cancer such as, but not restricted to, breast cancer, lungcancer, colorectal cancer, prostate cancer, ovarian cancer, endometrialcancer, gastric cancer, clear cell renal cell carcinoma, invasive ductalcarcinoma (breast), uveal melanoma, multiple myeloma, rhabdomyosarcoma,Ewing's sarcoma, Kaposi's sarcoma, pancreatic cancer, andmedulloblastoma.

In some embodiments are provided methods of treating ALK+ AnaplasticLarge Cell Lymphomas (ALCL) and possibly other indications in which theALK activity might play a role, like Neuroblastoma, Rhabdomyosarcoma,Glioblastoma, Inflammatory Myofibroblastic Tumor, and some kind ofMelanomas, Breast Carcinomas, Ewings sarcomas, Retinoblastomas andNon-Small Cell Lung Carcinomas (NSCLC).

In some embodiments are provided methods to treat, reduce the symptomsof, ameliorate the symptoms of, delay the onset of, or otherwisepharmaceutically address pancreatic cancer and possibly otherindications in which a defect in the modulation of ROS1 activity, orupregulation, misregulation or deletion thereof might play a role byadministering a pharmaceutical composition as provided herein.

In some embodiments are provided methods to treat, reduce the symptomsof, ameliorate the symptoms of, delay the onset of, or otherwisepharmaceutically address pancreatic cancer and possibly otherindications in which a defect in the modulation of ROS1 activity, orupregulation, misregulation or deletion thereof might play a role byadministering a by administering a pharmaceutical compositions asprovided herein. In some embodiments are provided methods to treat,reduce the symptoms of, ameliorate the symptoms of, delay the onset of,or otherwise pharmaceutically address pancreatic cancer and possiblyother indications in which a defect in the modulation of ROS1 activity,or upregulation, misregulation or deletion thereof might play a role byadministering a pharmaceutical composition as provided herein.

In some embodiments are provided methods to treat, reduce the symptomsof, ameliorate the symptoms of, delay the onset of, or otherwisepharmaceutically address pancreatic cancer and possibly otherindications in which a defect in the modulation of ALK, ROS1, TrkA,TrkB, or TrkC activity, or a combination thereof, or upregulation,misregulation or deletion thereof might play a role by administering apharmaceutical composition as provided herein. In some embodiments areprovided methods to treat, reduce the symptoms of, ameliorate thesymptoms of, delay the onset of, or otherwise pharmaceutically addresspancreatic cancer and possibly other indications in which a defect inthe modulation of ALK, ROS1, TrkA, TrkB, or TrkC activity, or acombination thereof, or upregulation, misregulation or deletion thereofmight play a role by administering a pharmaceutical composition asprovided herein.

In some embodiments are provided methods to treat, reduce the symptomsof, ameliorate the symptoms of, delay the onset of, or otherwisepharmaceutically address pancreatic cancer and possibly otherindications in which a defect in the modulation of ROS1 activity, orupregulation, misregulation or deletion thereof might play a role byadministering a pharmaceutical composition as provided herein. In someembodiments are provided methods to treat, reduce the symptoms of,ameliorate the symptoms of, delay the onset of, or otherwisepharmaceutically address pancreatic cancer and possibly otherindications in which a defect in the modulation of ROS1 activity, orupregulation, misregulation or deletion thereof might play a role byadministering a pharmaceutical composition as provided herein. In someembodiments are provided methods to treat, reduce the symptoms of,ameliorate the symptoms of, delay the onset of, or otherwisepharmaceutically address pancreatic cancer and possibly otherindications in which a defect in the modulation of ROS1 activity, orupregulation, misregulation or deletion thereof might play a role byadministering a pharmaceutical composition as provided herein.

In some embodiments are provided methods to treat, reduce the symptomsof, ameliorate the symptoms of, delay the onset of, or otherwisepharmaceutically address pancreatic cancer and possibly otherindications in which a defect in the modulation of ALK, ROS1, TrkA,TrkB, or TrkC activity, or a combination thereof, or upregulation,misregulation or deletion thereof might play a role by administeringpharmaceutical composition as provided herein. In some embodiments areprovided methods to treat, reduce the symptoms of, ameliorate thesymptoms of, delay the onset of, or otherwise pharmaceutically addresspancreatic cancer and possibly other indications in which a defect inthe modulation of ROS1, TrkA, TrkB, or TrkC activity, or a combinationthereof, activity, or upregulation, misregulation or deletion thereofmight play a role by administering a pharmaceutical composition asprovided herein.

In some embodiments are provided methods to treat, reduce the symptomsof, ameliorate the symptoms of, delay the onset of, or otherwisepharmaceutically address pancreatic cancer and possibly otherindications in which a defect in the modulation of ROS1, TrkA, TrkB, orTrkC activity, or a combination thereof, activity, or upregulation,misregulation or deletion thereof might play a role by administering apharmaceutical composition as provided herein. In some embodiments areprovided methods to treat, reduce the symptoms of, ameliorate thesymptoms of, delay the onset of, or otherwise pharmaceutically addresspancreatic cancer and possibly other indications in which a defect inthe modulation of ROS1, TrkA, TrkB, or TrkC activity, or a combinationthereof, activity, or upregulation, misregulation or deletion thereofmight play a role by administering a pharmaceutical composition asprovided herein. In some embodiments are provided methods to treat,reduce the symptoms of, ameliorate the symptoms of, delay the onset of,or otherwise pharmaceutically address pancreatic cancer and possiblyother indications in which a defect in the modulation of ROS1, TrkA,TrkB, or TrkC activity, or a combination thereof, activity, orupregulation, misregulation or deletion thereof might play a role byadministering a pharmaceutical composition as provided herein.

In some embodiments are provided methods to treat, reduce the symptomsof, ameliorate the symptoms of, delay the onset of, or otherwisepharmaceutically address pancreatic cancer associated with a ROS1down-regulation defect, for example a null mutation such as a ROS1deletion by identifying a ROS1 down-regulation defect, for example anull mutation such as a ROS1 deletion in a cancer or precancerouspancreatic cell in an subject, and administering to the subject apharmaceutical composition as provided herein. In some embodiments areprovided methods to treat, reduce the symptoms of, ameliorate thesymptoms of, delay the onset of, or otherwise pharmaceutically addresspancreatic cancer associated with a ROS1 down-regulation defect, forexample a null mutation such as a ROS1 deletion by identifying a ROS1down-regulation defect, for example a null mutation such as a ROS1deletion in a cancer or precancerous pancreatic cell in an subject, andadministering to the subject a pharmaceutical composition as providedherein. In some embodiments are provided methods to treat, reduce thesymptoms of, ameliorate the symptoms of, delay the onset of, orotherwise pharmaceutically address pancreatic cancer associated with aROS1 down-regulation defect, for example a null mutation such as a ROS1deletion by identifying a ROS1 down-regulation defect, for example anull mutation such as a ROS1 deletion in a cancer or precancerouspancreatic cell in an subject, and administering to the subject apharmaceutical composition as provided herein.

In some embodiments are provided methods to treat, reduce the symptomsof, ameliorate the symptoms of, delay the onset of, or otherwisepharmaceutically address pancreatic cancer associated with a ALK, ROS1,TrkA, TrkB, or TrkC down-regulation defect, for example a null mutationsuch as a ALK, ROS1, TrkA, TrkB, or TrkC deletion by identifying a ALK,ROS1, TrkA, TrkB, or TrkC down-regulation defect, for example a nullmutation such as a ALK, ROS1, TrkA, TrkB, or TrkC deletion in a canceror precancerous pancreatic cell in an subject, and administering to thesubject a pharmaceutical composition as provided herein.

In some embodiments identifying a ROS1 modulation defect such as anupregulation defect or a down-regulation defect, for example a nullmutation such as a ROS1 deletion or a ROS1 chimeric locus encoding aconstitutively active ROS1 kinase in a cancer or precancerous pancreaticcell in an subject comprises assaying for ROS1 activity in a cellextract from a pancreatic cancerous or precancerous cell population. Insome embodiments identifying a ROS1 modulation defect such as anupregulation defect or a down-regulation defect, for example a nullmutation such as a ROS1 deletion or a ROS1 chimeric locus encoding aconstitutively active ROS1 kinase in a cancer or precancerous pancreaticcell in an subject comprises assaying for ROS1 transcript accumulationin an RNA population from a pancreatic cancerous or precancerous cellpopulation. In some embodiments identifying a ROS1 modulation defectsuch as an upregulation defect or a down-regulation defect, for examplea null mutation such as a ROS1 deletion or a ROS1 chimeric locusencoding a constitutively active ROS1 kinase in a cancer or precancerouspancreatic cell in an subject comprises determining the nucleic acidsequence such as the genomic deoxyribonucleic acid sequence in a cell orcells or a cell population comprising a cell or cells from a pancreaticcancerous or precancerous cell population.

In some embodiments identifying a ALK, ROS1, TrkA, TrkB, or TrkCmodulation defect such as an upregulation defect or a down-regulationdefect, for example a null mutation such as a ALK, ROS1, TrkA, TrkB, orTrkC deletion or a ALK, ROS1, TrkA, TrkB, or TrkC chimeric locusencoding a constitutively active ALK, ROS1, TrkA, TrkB, or TrkC kinasein a cancer or precancerous pancreatic cell in an subject comprisesassaying for ALK, ROS1, TrkA, TrkB, or TrkC activity in a cell extractfrom a pancreatic cancerous or precancerous cell population. In someembodiments identifying a ALK, ROS1, TrkA, TrkB, or TrkC modulationdefect such as an upregulation defect or a down-regulation defect, forexample a null mutation such as a ALK, ROS1, TrkA, TrkB, or TrkCdeletion or a ALK, ROS1, TrkA, TrkB, or TrkC chimeric locus encoding aconstitutively active ALK, ROS1, TrkA, TrkB, or TrkC kinase in a canceror precancerous pancreatic cell in an subject comprises assaying forALK, ROS1, TrkA, TrkB, or TrkC transcript accumulation in an RNApopulation from a pancreatic cancerous or precancerous cell population.In some embodiments identifying a ALK, ROS1, TrkA, TrkB, or TrkCmodulation defect such as an upregulation defect or a down-regulationdefect, for example a null mutation such as a ALK, ROS1, TrkA, TrkB, orTrkC deletion or a ALK, ROS1, TrkA, TrkB, or TrkC chimeric locusencoding a constitutively active ALK, ROS1, TrkA, TrkB, or TrkC kinasein a cancer or precancerous pancreatic cell in an subject comprisesdetermining the nucleic acid sequence such as the genomicdeoxyribonucleic acid sequence in a cell or cells or a cell populationcomprising a cell or cells from a pancreatic cancerous or precancerouscell population.

In some embodiments are provided methods to treat, reduce the symptomsof, ameliorate the symptoms of, delay the onset of, or otherwisepharmaceutically address pancreatic cancer and possibly otherindications in which a defect in the modulation of ALK, ROS1, TrkA,TrkB, or TrkC activity, or a combination thereof, or upregulation,misregulation or deletion thereof might play a role by administering apharmaceutical composition as provided herein. In some embodiments areprovided methods to treat, reduce the symptoms of, ameliorate thesymptoms of, delay the onset of, or otherwise pharmaceutically addresspancreatic cancer and possibly other indications in which a defect inthe modulation of ROS1, TrkA, TrkB, or TrkC activity, or a combinationthereof, activity, or upregulation, misregulation or deletion thereofmight play a role by administering a pharmaceutical composition asprovided herein.

In some embodiments are provided methods to treat, reduce the symptomsof, ameliorate the symptoms of, delay the onset of, or otherwisepharmaceutically address pancreatic cancer and possibly otherindications in which a defect in the modulation of ROS1, TrkA, TrkB, orTrkC activity, or a combination thereof, activity, or upregulation,misregulation or deletion thereof might play a role by administering apharmaceutical composition as provided herein. In some embodiments areprovided methods to treat, reduce the symptoms of, ameliorate thesymptoms of, delay the onset of, or otherwise pharmaceutically addresspancreatic cancer and possibly other indications in which a defect inthe modulation of ROS1, TrkA, TrkB, or TrkC activity, or a combinationthereof, activity, or upregulation, misregulation or deletion thereofmight play a role by administering a pharmaceutical composition asprovided herein. In some embodiments are provided methods to treat,reduce the symptoms of, ameliorate the symptoms of, delay the onset of,or otherwise pharmaceutically address pancreatic cancer and possiblyother indications in which a defect in the modulation of ROS1, TrkA,TrkB, or TrkC activity, or a combination thereof, activity, orupregulation, misregulation or deletion thereof might play a role byadministering a pharmaceutical composition as provided herein.

In some embodiments are provided methods to treat, reduce the symptomsof, ameliorate the symptoms of, delay the onset of, or otherwisepharmaceutically address pancreatic cancer associated with a ROS1down-regulation defect, for example a null mutation such as a ROS1deletion by identifying a ROS1 down-regulation defect, for example anull mutation such as a ROS1 deletion in a cancer or precancerouspancreatic cell in an subject, and administering to the subject apharmaceutical composition as provided herein. In some embodiments areprovided methods to treat, reduce the symptoms of, ameliorate thesymptoms of, delay the onset of, or otherwise pharmaceutically addresspancreatic cancer associated with a ROS1 down-regulation defect, forexample a null mutation such as a ROS1 deletion by identifying a ROS1down-regulation defect, for example a null mutation such as a ROS1deletion in a cancer or precancerous pancreatic cell in an subject, andadministering to the subject a pharmaceutical composition as providedherein. In some embodiments are provided methods to treat, reduce thesymptoms of, ameliorate the symptoms of, delay the onset of, orotherwise pharmaceutically address pancreatic cancer associated with aROS1 down-regulation defect, for example a null mutation such as a ROS1deletion by identifying a ROS1 down-regulation defect, for example anull mutation such as a ROS1 deletion in a cancer or precancerouspancreatic cell in an subject, and administering to the subject apharmaceutical composition as provided herein.

In some embodiments are provided methods to treat, reduce the symptomsof, ameliorate the symptoms of, delay the onset of, or otherwisepharmaceutically address pancreatic cancer associated with a ALK, ROS1,TrkA, TrkB, or TrkC down-regulation defect, for example a null mutationsuch as a ALK, ROS1, TrkA, TrkB, or TrkC deletion by identifying a ALK,ROS1, TrkA, TrkB, or TrkC down-regulation defect, for example a nullmutation such as a ALK, ROS1, TrkA, TrkB, or TrkC deletion in a canceror precancerous pancreatic cell in an subject, and administering to thesubject a pharmaceutical composition as provided herein.

In some embodiments identifying a ROS1 modulation defect such as anupregulation defect or a down-regulation defect, for example a nullmutation such as a ROS1 deletion or a ROS1 chimeric locus encoding aconstitutively active ROS1 kinase in a cancer or precancerous pancreaticcell in an subject comprises assaying for ROS1 activity in a cellextract from a pancreatic cancerous or precancerous cell population. Insome embodiments identifying a ROS1 modulation defect such as anupregulation defect or a down-regulation defect, for example a nullmutation such as a ROS1 deletion or a ROS1 chimeric locus encoding aconstitutively active ROS1 kinase in a cancer or precancerous pancreaticcell in an subject comprises assaying for ROS1 transcript accumulationin an RNA population from a pancreatic cancerous or precancerous cellpopulation. In some embodiments identifying a ROS1 modulation defectsuch as an upregulation defect or a down-regulation defect, for examplea null mutation such as a ROS1 deletion or a ROS1 chimeric locusencoding a constitutively active ROS1 kinase in a cancer or precancerouspancreatic cell in an subject comprises determining the nucleic acidsequence such as the genomic deoxyribonucleic acid sequence in a cell orcells or a cell population comprising a cell or cells from a pancreaticcancerous or precancerous cell population.

In some embodiments identifying a ALK, ROS1, TrkA, TrkB, or TrkCmodulation defect such as an upregulation defect or a down-regulationdefect, for example a null mutation such as a ALK, ROS1, TrkA, TrkB, orTrkC deletion or a ALK, ROS1, TrkA, TrkB, or TrkC chimeric locusencoding a constitutively active ALK, ROS1, TrkA, TrkB, or TrkC kinasein a cancer or precancerous pancreatic cell in an subject comprisesassaying for ALK, ROS1, TrkA, TrkB, or TrkC activity in a cell extractfrom a pancreatic cancerous or precancerous cell population. In someembodiments identifying a ALK, ROS1, TrkA, TrkB, or TrkC modulationdefect such as an upregulation defect or a down-regulation defect, forexample a null mutation such as a ALK, ROS1, TrkA, TrkB, or TrkCdeletion or a ALK, ROS1, TrkA, TrkB, or TrkC chimeric locus encoding aconstitutively active ALK, ROS1, TrkA, TrkB, or TrkC kinase in a canceror precancerous pancreatic cell in an subject comprises assaying forALK, ROS1, TrkA, TrkB, or TrkC transcript accumulation in an RNApopulation from a pancreatic cancerous or precancerous cell population.In some embodiments identifying a ALK, ROS1, TrkA, TrkB, or TrkCmodulation defect such as an upregulation defect or a down-regulationdefect, for example a null mutation such as a ALK, ROS1, TrkA, TrkB, orTrkC deletion or a ALK, ROS1, TrkA, TrkB, or TrkC chimeric locusencoding a constitutively active ALK, ROS1, TrkA, TrkB, or TrkC kinasein a cancer or precancerous pancreatic cell in an subject comprisesdetermining the nucleic acid sequence such as the genomicdeoxyribonucleic acid sequence in a cell or cells or a cell populationcomprising a cell or cells from a pancreatic cancerous or precancerouscell population.

In some embodiments are provided methods to treat, reduce the symptomsof, ameliorate the symptoms of, delay the onset of, or otherwisepharmaceutically address a condition selected from non-small cell lungcancer, papillary thyroid cancer, neuroblastoma, pancreatic cancer andcolorectal cancer and possibly other indications in which a defect inthe modulation of ALK, ROS1, TrkA, TrkB, or TrkC activity, or acombination thereof, or upregulation, misregulation or deletion thereofmight play a role by administering pharmaceutical composition asprovided herein. In some embodiments are provided methods to treat,reduce the symptoms of, ameliorate the symptoms of, delay the onset of,or otherwise pharmaceutically address pancreatic cancer and possiblyother indications in which a defect in the modulation of ROS1, TrkA,TrkB, or TrkC activity, or a combination thereof, activity, orupregulation, misregulation or deletion thereof might play a role byadministering a pharmaceutical composition as provided herein.

In some embodiments are provided methods to treat, reduce the symptomsof, ameliorate the symptoms of, delay the onset of, or otherwisepharmaceutically address a condition selected from non-small cell lungcancer, papillary thyroid cancer, neuroblastoma, pancreatic cancer andcolorectal cancer and possibly other indications in which a defect inthe modulation of ROS1, TrkA, TrkB, or TrkC activity, or a combinationthereof, activity, or upregulation, misregulation or deletion thereofmight play a role by administering a pharmaceutical composition asprovided herein. In some embodiments are provided methods to treat,reduce the symptoms of, ameliorate the symptoms of, delay the onset of,or otherwise pharmaceutically address a condition selected fromnon-small cell lung cancer, papillary thyroid cancer, neuroblastoma,pancreatic cancer and colorectal cancer and possibly other indicationsin which a defect in the modulation of ROS1, TrkA, TrkB, or TrkCactivity, or a combination thereof, activity, or upregulation,misregulation or deletion thereof might play a role by administering apharmaceutical composition as provided herein. In some embodiments areprovided methods to treat, reduce the symptoms of, ameliorate thesymptoms of, delay the onset of, or otherwise pharmaceutically address acondition selected from non-small cell lung cancer, papillary thyroidcancer, neuroblastoma, pancreatic cancer and colorectal cancer andpossibly other indications in which a defect in the modulation of ROS1,TrkA, TrkB, or TrkC activity, or a combination thereof, activity, orupregulation, misregulation or deletion thereof might play a role byadministering a pharmaceutical composition as provided herein.

In some embodiments are provided methods to treat, reduce the symptomsof, ameliorate the symptoms of, delay the onset of, or otherwisepharmaceutically address a condition selected from non-small cell lungcancer, papillary thyroid cancer, neuroblastoma, pancreatic cancer andcolorectal cancer associated with a ROS1 down-regulation defect, forexample a null mutation such as a ROS1 deletion by identifying a ROS1down-regulation defect, for example a null mutation such as a ROS1deletion in a cancer or precancerous cell in an subject, andadministering to the subject a pharmaceutical composition as providedherein. In some embodiments are provided methods to treat, reduce thesymptoms of, ameliorate the symptoms of, delay the onset of, orotherwise pharmaceutically address a condition selected from non-smallcell lung cancer, papillary thyroid cancer, neuroblastoma, pancreaticcancer and colorectal cancer associated with a ROS1 down-regulationdefect, for example a null mutation such as a ROS1 deletion byidentifying a ROS1 down-regulation defect, for example a null mutationsuch as a ROS1 deletion in a cancer or precancerous cell in an subject,and administering to the subject a pharmaceutical composition asprovided herein. In some embodiments are provided methods to treat,reduce the symptoms of, ameliorate the symptoms of, delay the onset of,or otherwise pharmaceutically address a condition selected fromnon-small cell lung cancer, papillary thyroid cancer, neuroblastoma,pancreatic cancer and colorectal cancer associated with a ROS1down-regulation defect, for example a null mutation such as a ROS1deletion by identifying a ROS1 down-regulation defect, for example anull mutation such as a ROS1 deletion in a cancer or precancerous cellin an subject, and administering to the subject a pharmaceuticalcomposition as provided herein.

In some embodiments are provided methods to treat, reduce the symptomsof, ameliorate the symptoms of, delay the onset of, or otherwisepharmaceutically address a condition selected from non-small cell lungcancer, papillary thyroid cancer, neuroblastoma, pancreatic cancer andcolorectal cancer associated with a ALK, ROS1, TrkA, TrkB, or TrkCdown-regulation defect, for example a null mutation such as a ALK, ROS1,TrkA, TrkB, or TrkC deletion by identifying a ALK, ROS1, TrkA, TrkB, orTrkC down-regulation defect, for example a null mutation such as a ALK,ROS1, TrkA, TrkB, or TrkC deletion in a cancer or precancerous cell inan subject, and administering to the subject a pharmaceuticalcomposition as provided herein.

In some embodiments identifying a ROS1 modulation defect such as anupregulation defect or a down-regulation defect, for example a nullmutation such as a ROS1 deletion or a ROS1 chimeric locus encoding aconstitutively active ROS1 kinase in a cancer or precancerous cell in ansubject comprises assaying for ROS1 activity in a cell extract from apancreatic cancerous or precancerous cell population. In someembodiments identifying a ROS1 modulation defect such as an upregulationdefect or a down-regulation defect, for example a null mutation such asa ROS1 deletion or a ROS1 chimeric locus encoding a constitutivelyactive ROS1 kinase in a cancer or precancerous cell in an subjectcomprises assaying for ROS1 transcript accumulation in an RNA populationfrom a cancerous or precancerous cell population. In some embodimentsidentifying a ROS1 modulation defect such as an upregulation defect or adown-regulation defect, for example a null mutation such as a ROS1deletion or a ROS1 chimeric locus encoding a constitutively active ROS1kinase in a cancer or precancerous cell in an subject comprisesdetermining the nucleic acid sequence such as the genomicdeoxyribonucleic acid sequence in a cell or cells or a cell populationcomprising a cell or cells from a pancreatic cancerous or precancerouscell population.

In some embodiments identifying a ALK, ROS1, TrkA, TrkB, or TrkCmodulation defect such as an upregulation defect or a down-regulationdefect, for example a null mutation such as a ALK, ROS1, TrkA, TrkB, orTrkC deletion or a ALK, ROS1, TrkA, TrkB, or TrkC chimeric locusencoding a constitutively active ALK, ROS1, TrkA, TrkB, or TrkC kinasein a cancer or precancerous cell in an subject comprises assaying forALK, ROS1, TrkA, TrkB, or TrkC activity in a cell extract from acancerous or precancerous cell population. In some embodimentsidentifying a ALK, ROS1, TrkA, TrkB, or TrkC modulation defect such asan upregulation defect or a down-regulation defect, for example a nullmutation such as a ALK, ROS1, TrkA, TrkB, or TrkC deletion or a ALK,ROS1, TrkA, TrkB, or TrkC chimeric locus encoding a constitutivelyactive ALK, ROS1, TrkA, TrkB, or TrkC kinase in a cancer or precancerouscell in an subject comprises assaying for ALK, ROS1, TrkA, TrkB, or TrkCtranscript accumulation in an RNA population from a cancerous orprecancerous cell population. In some embodiments identifying a ALK,ROS1, TrkA, TrkB, or TrkC modulation defect such as an upregulationdefect or a down-regulation defect, for example a null mutation such asa ALK, ROS1, TrkA, TrkB, or TrkC deletion or a ALK, ROS1, TrkA, TrkB, orTrkC chimeric locus encoding a constitutively active ALK, ROS1, TrkA,TrkB, or TrkC kinase in a cancer or precancerous cell in an subjectcomprises determining the nucleic acid sequence such as the genomicdeoxyribonucleic acid sequence in a cell or cells or a cell populationcomprising a cell or cells from a cancerous or precancerous cellpopulations.

In some embodiments are provided methods for inhibiting at least one ofALK, ROS1, TrkA, TrkB, or TrkC kinase activity, or a combinationthereof, in a cell, comprising contacting said cell with an effectiveamount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide.Some embodiments provide methods of inhibiting at least one of ALK,ROS1, TrkA, TrkB, or TrkC kinase activity, or a combination thereof, ina cell, by contacting the cell with an effective amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide.Some embodiments provide methods of inhibiting at least one of ALK,ROS1, TrkA, TrkB, or TrkC kinase activity, or a combination thereof, ina cell, comprising contacting said cell with an effective amount of acompound which isN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide.In some embodiments, theN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideis delivered to the cell in the form of a pharmaceutical composition asprovided herein.

Some embodiments provide methods of inhibiting ALK, ROS1, TrkA, TrkB, orTrkC activity, or a combination thereof, in a subject, comprisingadministering to said subject a pharmaceutical composition as providedherein that comprises an effective amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide.

Some embodiments provide methods of treating cancer in a subject in needthereof, the method comprising inhibiting ALK, ROS1, TrkA, TrkB, or TrkCactivity, or a combination thereof, in said subject, by administering tosaid subject a pharmaceutical composition as provided herein thatcomprises an effective amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide.

Some embodiments provide methods of treating non-small cell lung cancer,papillary thyroid cancer, neuroblastoma, pancreatic cancer or colorectalcancer in a subject, comprising administering to said subject apharmaceutical composition as provided herein that comprises aneffective amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide.

Some embodiments provide methods of treating tumors in a subject, saidmethods comprising administering to the subject a pharmaceuticalcomposition as provided herein that comprises an effective amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide.

Some embodiments provide methods wherein the tumors are caused by thepresence of non-small cell lung cancer, papillary thyroid cancer,neuroblastoma, pancreatic cancer or colorectal cancer in the subject.Some embodiments provide methods wherein one or more of the cellscomprising the tumors in the subject test positive for the presence of agene that expresses at least one of ALK, ROS1, TrkA, TrkB, or TrkCkinase or one or more of the cells comprising the tumors in said subjectdemonstrates at least one of ALK, ROS1, TrkA, TrkB, or TrkC kinaseactivity.

Some embodiments provide methods wherein one or more of the cellscomprising the tumors in the subject test positive for at least one generearrangement comprising the gene, or a fragment thereof, that expressesat least one of ALK, ROS1, TrkA, TrkB, or TrkC kinase. Some embodimentsprovide such methods wherein the cells test positive for at least one ofROS1, TrkA, TrkB, or TrkC kinases. Some embodiments provide methodswherein the cells test positive for ROS1 kinase. Some embodimentsprovide methods wherein the cells test positive for at least one ofTrkA, TrkB and TrkC kinase. Some embodiments provide methods wherein thecells test positive for TrkA kinase. Some embodiments provide methodswherein the cells test positive for TrkB kinase. Some embodimentsprovide such methods wherein the cells test positive for TrkC kinase.

Some embodiments provide methods of treating cancer in a subject, themethod comprising: (1) testing one or more cells comprising the tumorsin the subject for the presence of at least one of ALK, ROS1, TrkA,TrkB, or TrkC kinase; and (2) administering to the subject apharmaceutical composition as provided herein that comprises aneffective amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideif said one or more cells tests positive for at least one of ALK, ROS1,TrkA, TrkB, or TrkC kinase.

Some embodiments provide methods of treating cancer in a subject, themethod comprising: (1) testing one or more cells comprising the tumorsin the subject for the presence of at least one of ROS1, TrkA, TrkB, orTrkC kinase; and (2) administering to the subject a pharmaceuticalformulation as provided herein that comprises an effective amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideif said one or more cells tests positive for at least one of ROS1, TrkA,TrkB, or TrkC kinase.

Some embodiments provide methods of treating cancer in a subject,wherein one or more cancerous cells in said subject express at least oneof ROS1, TrkA, TrkB, or TrkC kinase, the method comprising administeringto the subject a pharmaceutical composition as provided herein thatcomprises an effective amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide,

Some embodiments provide methods of treating cancer in a subject,wherein one or more cancerous cells in said subject express at least oneof ROS1, TrkA, TrkB, or TrkC kinase, the method comprising administeringto the subject a pharmaceutical composition as provided herein thatcomprises an effective amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide.

Some embodiments provide a method for treating a subject having cancer,wherein tumors from said subject are ALK, ROS1, TrkA, TrkB, or TrkCpositive, or a combination thereof, the method comprising administeringto the subject a pharmaceutical composition as provided herein thatcomprises an effective amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide.

Some embodiments provide a method for treating a subject having ALK,ROS1, TrkA, TrkB, or TrkC positive cancer, or a combination thereof, themethod comprising administering to the subject a pharmaceuticalformulation as provided herein that comprises an effective amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide.

Some embodiments provide a method of treating a cancer subject,comprising (a) acquiring knowledge of the presence of at least onegenetic alteration in at least one target gene in the cancer subject,wherein the at least one target gene is selected from ALK1, BDNF, NGF,NGFR, NTF3, NTF4, ROS1, SORT1, NTRK1, NTRK2, and NTRK3; and (b)administering a pharmaceutical composition as provided herein to saidcancer subject, said pharmaceutical composition comprising atherapeutically effective amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide.

Some embodiments provide a method of treating a cancer subject,comprising administering to said cancer subject a pharmaceuticalcomposition as provided herein that comprises a therapeuticallyeffective amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide,wherein prior to said administration of said pharmaceutical composition,said cancer subject is known to possess at least one genetic alterationin at least one target gene selected from ALK1, BDNF, NGF, NGFR, NTF3,NTF4, ROS1, SORT1, NTRK1, NTRK2, and NTRK3.

Some embodiments provide a method of treating cancer in a subject,comprising administering to said cancer subject known to possess atleast one genetic alteration in at least one target gene selected fromALK1, BDNF, NGF, NGFR, NTF3, NTF4, ROS1, SORT1, NTRK1, NTRK2, and NTRK3a pharmaceutical composition as provided herein that comprises atherapeutically effective amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide.

Some embodiments provide a method of treating a cancer subject, whereinsaid cancer subject is known to possess at least one genetic alterationin at least one target gene, comprising administering to said cancersubject a pharmaceutical compositions comprising a therapeuticallyeffective amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide,and wherein said target gene is selected from ALK1, BDNF, NGF, NGFR,NTF3, NTF4, ROS1, SORT1, NTRK1, NTRK2, and NTRK3.

Some embodiments provide a method of treating a cancer subject, whereinprior to said treatment said subject is known to possess at least onegenetic alteration in at least one target gene, comprising administeringto said cancer subject a pharmaceutical composition as provided hereinthat comprises a therapeutically effective amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide,and wherein said target gene is selected from ALK1, BDNF, NGF, NGFR,NTF3, NTF4, ROS1, SORT1, NTRK1, NTRK2, and NTRK3.

Some embodiments provide a method of treating a cancer subject,comprising administering to said cancer subject a pharmaceuticalcomposition as provided herein that comprises a therapeuticallyeffective amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide,and wherein prior to said pharmaceutical composition being administeredto said subject, said subject is known to possess at least one geneticalteration in at least one target gene selected from ALK1, BDNF, NGF,NGFR, NTF3, NTF4, ROS1, SORT1, NTRK1, NTRK2, and NTRK3.

Some embodiments provide a method for treating a cancer subject,comprising (a) acquiring knowledge of the presence of at least onegenetic alteration in at least one target gene selected from ALK1, BDNF,NGF, NGFR, NTF3, NTF4, ROS1, SORT1, NTRK1, NTRK2, and NTRK3; and (b)administering to said subject a pharmaceutical composition as providedherein that comprises a therapeutically effective amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide.

Some embodiments provide any of the methods described herein wherein thesubject or subject is suffering from cancer and the cancer is selectedfrom at least one of non-small cell lung cancer, papillary thyroidcancer, neuroblastoma, pancreatic cancer and colorectal cancer. Someembodiments provide any of the methods described herein wherein thesubject or subject is suffering from non-small cell lung cancer. Someembodiments provide any of the methods described herein wherein thesubject or subject is suffering from papillary thyroid cancer. Someembodiments provide any of the methods described herein wherein thesubject or subject is suffering from neuroblastoma. Some embodimentsprovide any of the methods described herein wherein the subject orsubject is suffering from pancreatic cancer. Some embodiments provideany of the methods described herein wherein the subject or subject issuffering from colorectal cancer.

In some embodiments, the pharmaceutical compositions provided herein maybe used in combination with one or more additional anti-cancer agentswhich are described below. When a combination therapy is used, the oneor more additional anti-cancer agents may be administered sequentiallyor simultaneously with the pharmaceutical compositions provided herein.In some embodiments, the additional anti-cancer agent is administered toa mammal (e.g., a human) prior to administration of the pharmaceuticalcompositions provided herein. In some embodiments, the additionalanti-cancer agent is administered to the mammal after administration ofthe pharmaceutical compositions provided herein. In some embodiments,the additional anti-cancer agent is administered to the mammal (e.g., ahuman) simultaneously with the administration of pharmaceuticalcompositions provided herein.

Some embodiments also relate to pharmaceutical compositions for thetreatment of abnormal cell growth in a mammal, comprising a human, whichcomprises an amount of one or more pharmaceutical compositions providedherein comprising hydrates, solvates and polymorphs ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein combination with one or more (preferably one to three) anti-canceragents selected from the group consisting of anti-angiogenesis agentsand signal transduction inhibitors and a pharmaceutically acceptablecarrier, wherein the amounts ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand the combination anti-cancer agents when taken as a whole istherapeutically effective for treating said abnormal cell growth.

In some embodiments, the anti-cancer agent used in conjunction with thepharmaceutical compositions described herein is an anti-angiogenesisagent (e.g., an agent that stops tumors from developing new bloodvessels). Examples of anti-angiogenesis agents include for example VEGFinhibitors, VEGFR inhibitors, TIE-2 inhibitors, PDGFR inhibitors,angiopoetin inhibitors, PKC-beta inhibitors, COX-2 (cyclooxygenase II)inhibitors, integrins (alpha-v/beta-3), MMP-2 (matrix-metalloproteinase2) inhibitors, and MMP-9 (matrix-metalloproteinase 9) inhibitors.Preferred anti-angiogenesis agents include sunitinib (Sutent®),bevacizumab (Avastin®), axitinib (AG 13736), SU 14813 (Pfizer), and AG13958 (Pfizer).

Additional anti-angiogenesis agents include vatalanib (CGP 79787),Sorafenib (Nexavar®), pegaptanib octasodium (Macugen®), vandetanib(Zactima®), PF-0337210 (Pfizer), SU 14843 (Pfizer), AZD 2171(AstraZeneca), ranibizumab (Lucentis®), Neovastat® (AE 941),tetrathiomolybdata (Coprexa®), AMG 706 (Amgen), VEGF Trap (AVE 0005),CEP 7055 (Sanofi-Aventis), XL 880 (Exelixis), telatinib (BAY 57-9352),and CP-868,596 (Pfizer).

Other anti-angiogenesis agents include enzastaurin (LY 317615),midostaurin (CGP 41251), perifosine (KRX 0401), teprenone (Selbex®) andUCN 01 (Kyowa Hakko).

Other examples of anti-angiogenesis agents which can be used inconjunction with one or more pharmaceutical compositions describedherein include celecoxib (Celebrex®), parecoxib (Dynastat®), deracoxib(SC 59046), lumiracoxib (Preige®), valdecoxib (Bextra®), rofecoxib(Vioxx®), iguratimod (Careram®), IP 751 (Invedus), SC-58125 (Pharmacia)and etoricoxib (Arcoxia®).

Other anti-angiogenesis agents include exisulind (Aptosyn®), salsalate(Amigesic®), diflunisal (Dolobid®), ibuprofen (Motrin®), ketoprofen(Orudis®) nabumetone (Relafen®), piroxicam (Feldene®), naproxen (Aleve®,Naprosyn®) diclofenac (Voltaren®), indomethacin (Indocin®), sulindac(Clinoril®), tolmetin (Tolectin®), etodolac (Lodine®), ketorolac(Toradol®), and oxaprozin (Daypro®).

Other anti-angiogenesis agents include ABT 510 (Abbott), apratastat (TMI005), AZD 8955 (AstraZeneca), incyclinide (Metastat®), and PCK 3145(Procyon).

Other anti-angiogenesis agents include acitretin (Neotigason®),plitidepsin (Aplidine®), cilengtide (EMD 121974), combretastatin A4(CA4P), fenretinide (4 HPR), halofuginone (Tempostatin®), Panzem®(2-methoxyestradiol), PF-03446962 (Pfizer), rebimastat (BMS 275291),catumaxomab (Removab®), lenalidomide (Revlimid®) squalamine (EVIZON®),thalidomide (Thalomid®), Ukrain® (NSC 631570), Vitaxin® (MEDI 522), andzoledronic acid (Zometa®).

In some embodiments, the anti-cancer agent is a so called signaltransduction inhibitor (e.g., inhibiting the means by which regulatorymolecules that govern the fundamental processes of cell growth,differentiation, and survival communicated within the cell). Signaltransduction inhibitors include small molecules, antibodies, andantisense molecules. Signal transduction inhibitors include for examplekinase inhibitors (e.g., tyrosine kinase inhibitors or serine/threoninekinase inhibitors) and cell cycle inhibitors. More specifically signaltransduction inhibitors include, for example, ALK inhibitors, ROS1inhibitors, TrkA inhibitors, TrkB inhibitors, TrkC inhibitors, farnesylprotein transferase inhibitors, EGF inhibitor, ErbB-1 (EGFR), ErbB-2,pan erb, IGF1R inhibitors, MEK, c-Kit inhibitors, FLT-3 inhibitors,K-Ras inhibitors, PI3 kinase inhibitors, JAK inhibitors, STATinhibitors, Raf kinase inhibitors, Akt inhibitors, mTOR inhibitor, P70S6kinase inhibitors, inhibitors of the WNT pathway and so calledmulti-targeted kinase inhibitors.

Preferred signal transduction inhibitors include gefitinib (Iressa®),cetuximab (Erbitux®), erlotinib (Tarceva®), trastuzumab (Herceptin®),sunitinib (Sutent®) imatinib (Gleevec®), and PD325901 (Pfizer).

Additional examples of signal transduction inhibitors which may be usedin conjunction with one or more pharmaceutical compositions providedherein include BMS 214662 (Bristol-Myers Squibb), lonafarnib (Sarasar®),pelitrexol (AG 2037), matuzumab (EMD 7200), nimotuzumab (TheraCIMh-R3®), panitumumab (Vectibix®), Vandetanib (Zactima®), pazopanib (SB786034), ALT 110 (Alteris Therapeutics), BMW 2992 (BoehringerIngelheim), and Cervene® (TP 38).

Other examples of signal transduction inhibitor include PF-2341066(Pfizer), PF-299804 (Pfizer), canertinib (CI 1033), pertuzumab(Omnitarg®), Lapatinib (Tycerb®), pelitinib (EKB 569), miltefosine(Miltefosin®), BMS 599626 (Bristol-Myers Squibb), Lapuleucel-T(Neuvenge®), NeuVax® (E75 cancer vaccine), Osidem® (IDM 1), mubritinib(TAK-165), CP-724,714 (Pfizer), panitumumab (Vectibix®), lapatinib(Tycerb®), PF-299804 (Pfizer), pelitinib (EKB 569), and pertuzumab(Omnitarg®).

Other examples of signal transduction inhibitors include ARRY 142886(Array Biopharm), everolimus (Certican®), zotarolimus (Endeavor®),temsirolimus (Torisel®), AP 23573 (ARIAD), and VX 680 (Vertex).

Additionally, other signal transduction inhibitors include XL 647(Exelixis), sorafenib (Nexavar®), LE-AON (Georgetown University), andGI-4000 (GlobeImmune).

Other signal transduction inhibitors include ABT 751 (Abbott), alvocidib(flavopiridol), BMS 387032 (Bristol Myers), EM 1421 (Erimos), indisulam(E 7070), seliciclib (CYC 200), BIO 112 (One Bio), BMS 387032(Bristol-Myers Squibb), PD 0332991 (Pfizer), AG 024322 (Pfizer), LOXO-101 (Loxo Oncology), crizotinib, and ceritinib.

In some embodiments, the pharmaceutical compositions provided herein areused together with classical antineoplastic agents. Classicalantineoplastic agents include but are not limited to hormonal modulatorssuch as hormonal, anti-hormonal, androgen agonist, androgen antagonistand anti-estrogen therapeutic agents, histone deacetylase (HDAC)inhibitors, gene silencing agents or gene activating agents,ribonucleases, proteosomics, Topoisomerase I inhibitors, Camptothecinderivatives, Topoisomerase II inhibitors, alkylating agents,antimetabolites, poly(ADP-ribose) polymerase-1 (PARP-1) inhibitor,microtubulin inhibitors, antibiotics, plant derived spindle inhibitors,platinum-coordinated compounds, gene therapeutic agents, antisenseoligonucleotides, vascular targeting agents (VTAs), and statins.

Examples of classical antineoplastic agents used in combination therapywith one or more pharmaceutical compositions provided herein optionallywith one or more other agents include, but are not limited to,glucocorticoids, such as dexamethasone, prednisone, prednisolone,methylprednisolone, hydrocortisone, and progestins such asmedroxyprogesterone, megestrol acetate (Megace), mifepristone (RU-486),Selective Estrogen Receptor Modulators (SERMs; such as tamoxifen,raloxifene, lasofoxifene, afimoxifene, arzoxifene, bazedoxifene,fispemifene, ormeloxifene, ospemifene, tesmilifene, toremifene,trilostane and CHF 4227 (Cheisi)), Selective Estrogen-ReceptorDownregulators (SERD's; such as fulvestrant), exemestane (Aromasin),anastrozole (Arimidex), atamestane, fadrozole, letrozole (Femara),gonadotropin-releasing hormone (GnRH; also commonly referred to asluteinizing hormone-releasing hormone [LHRH]) agonists such as buserelin(Suprefact), goserelin (Zoladex), leuprorelin (Lupron), and triptorelin(Trelstar), abarelix (Plenaxis), bicalutamide (Casodex), cyproterone,flutamide (Eulexin), megestrol, nilutamide (Nilandron), and osaterone,dutasteride, epristeride, finasteride, Serenoa repens, PHL 00801,abarelix, goserelin, leuprorelin, triptorelin, bicalutamide, tamoxifen,exemestane, anastrozole, fadrozole, formestane, letrozole, andcombinations thereof.

Other examples of classical antineoplastic agents used in combinationwith pharmaceutical compositions provided herein include, but are notlimited to, suberolanilide hydroxamic acid (SAHA, Merck Inc./AtonPharmaceuticals), depsipeptide (FR901228 or FK228), G2M-777, MS-275,pivaloyloxymethyl butyrate and PXD-101; Onconase (ranpirnase), PS-341(MLN-341), Velcade (bortezomib), 9-aminocamptothecin, belotecan,BN-80915 (Roche), camptothecin, diflomotecan, edotecarin, exatecan(Daiichi), gimatecan, 10-hydroxycamptothecin, irinotecan HCl(Camptosar), lurtotecan, Orathecin (rubitecan, Supergen), SN-38,topotecan, camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin,irinotecan, SN-38, edotecarin, topotecan, aclarubicin, paclitaxel,amonafide, amrubicin, annamycin, daunorubicin, doxorubicin,elsamitrucin, epirubicin, etoposide, idarubicin, galarubicin,hydroxycarbamide, nemorubicin, novantrone (mitoxantrone), pirarubicin,pixantrone, procarbazine, rebeccamycin, sobuzoxane, tafluposide,valrubicin, Zinecard (dexrazoxane), nitrogen mustard N-oxide,cyclophosphamide, AMD-473, altretamine, AP-5280, apaziquone,brostallicin, bendamustine, busulfan, carboquone, carmustine,chlorambucil, dacarbazine, estramustine, fotemustine, glufosfamide,ifosfamide, KW-2170, lomustine, mafosfamide, mechlorethamine, melphalan,mitobronitol, mitolactol, mitomycin C, mitoxatrone, nimustine,ranimustine, temozolomide, thiotepa, and platinum-coordinated alkylatingcompounds such as cisplatin, Paraplatin (carboplatin), eptaplatin,lobaplatin, nedaplatin, Eloxatin (oxaliplatin, Sanofi), streptozocin,satrplatin, and combinations thereof.

In some embodiments, the pharmaceutical compositions provided herein areused together with dihydrofolate reductase inhibitors (such asmethotrexate and NeuTrexin (trimetrexate)), purine antagonists (such as6-mercaptopurine riboside, mercaptopurine, 6-thioguanine, cladribine,clofarabine (Clolar), fludarabine, nelarabine, and raltitrexed),pyrimidine antagonists (such as 5-fluorouracil (5-FU), Alimta(premetrexed disodium, LY231514, MTA), capecitabine (Xeloda®), cytosinearabinoside, Gemzar® (gemcitabine, Eli Lilly), Tegafur (UFT Orzel orUforal and including TS-1 combination of tegafur, gimestat and otostat),doxifluridine, carmofur, cytarabine (including ocfosfate, phosphatestearate, sustained release and liposomal forms), enocitabine,5-azacitidine (Vidaza), decitabine, and ethynylcytidine) and otherantimetabolites such as eflornithine, hydroxyurea, leucovorin,nolatrexed (Thymitaq), triapine, trimetrexate,N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamicacid, AG-014699 (Pfizer Inc.), ABT-472 (Abbott Laboratories), INO-1001(Inotek Pharmaceuticals), KU-0687 (KuDOS Pharmaceuticals) and GPI 18180(Guilford Pharm Inc) and combinations thereof.

Other examples of classical antineoplastic cytotoxic agents used incombination therapy with one or more pharmaceutical compositionsprovided herein optionally with one or more other agents include, butare not limited to, Abraxane (Abraxis BioScience, Inc.), Batabulin(Amgen), EPO 906 (Novartis), Vinflunine (Bristol-Myers Squibb Company),actinomycin D, bleomycin, mitomycin C, neocarzinostatin (Zinostatin),vinblastine, vincristine, vindesine, vinorelbine (Navelbine), docetaxel(Taxotere), Ortataxel, paclitaxel (including Taxoprexin a DHA/paclitaxelconjugate), cisplatin, carboplatin, Nedaplatin, oxaliplatin (Eloxatin),Satraplatin, Camptosar, capecitabine (Xeloda), oxaliplatin (Eloxatin),Taxotere alitretinoin, Canfosfamide (Telcyta®), DMXAA (Antisoma),ibandronic acid, L-asparaginase, pegaspargase (Oncaspar®), Efaproxiral(Efaproxyn®—radiation therapy)), bexarotene (Targretin®), Tesmilifene(DPPE—enhances efficacy of cytotoxics)), Theratope® (Biomira), Tretinoin(Vesanoid®), tirapazamine (Trizaone®), motexafin gadolinium (Xcytrin®)Cotara® (mAb), and NBI-3001 (Protox Therapeutics),polyglutamate-paclitaxel (Xyotax®) and combinations thereof.

Further examples of classical antineoplastic agents used in combinationtherapy with one or more pharmaceutical compositions provided hereinoptionally with one or more other agents include, but are not limitedto, as Advexin (ING 201), TNFerade (GeneVec, one or more compounds whichexpress TNFalpha in response to radiotherapy), RB94 (Baylor College ofMedicine), Genasense (Oblimersen, Genta), Combretastatin A4P (CA4P),Oxi-4503, AVE-8062, ZD-6126, TZT-1027, Atorvastatin (Lipitor, PfizerInc.), Provastatin (Pravachol, Bristol-Myers Squibb), Lovastatin(Mevacor, Merck Inc.), Simvastatin (Zocor, Merck Inc.), Fluvastatin(Lescol, Novartis), Cerivastatin (Baycol, Bayer), Rosuvastatin (Crestor,AstraZeneca), Lovostatin, Niacin (Advicor, Kos Pharmaceuticals), Caduet,Lipitor, torcetrapib, and combinations thereof.

Some embodiments relate to a method for the treatment of breast cancerin a human in need of such treatment. In some embodiments, the methodincludes, for example, administering to said human an amount of one ormore pharmaceutical compositions provided herein in combination with oneor more (preferably one to three) anti-cancer agents selected from thegroup consisting of trastuzumab, tamoxifen, docetaxel, paclitaxel,capecitabine, gemcitabine, vinorelbine, exemestane, letrozole andanastrozole.

Some embodiments provide a method of treating colorectal cancer in amammal, such as a human, in need of such treatment, by administering anamount of one or more pharmaceutical compositions provided herein incombination with one or more (preferably one to three) anti-canceragents. Examples of particular anti-cancer agents include thosetypically used in adjuvant chemotherapy, such as FOLFOX, a combinationof 5-fluorouracil (5-FU) or capecitabine (Xeloda), leucovorin andoxaliplatin (Eloxatin). Further examples of particular anti-canceragents include those typically used in chemotherapy for metastaticdisease, such as FOLFOX or FOLFOX in combination with bevacizumab(Avastin); and FOLFIRI, a combination of 5-FU or capecitabine,leucovorin and irinotecan (Camptosar). Further examples include 17-DMAG,ABX-EFR, AMG-706, AMT-2003, ANX-510 (CoFactor), aplidine (plitidepsin,Aplidin), Aroplatin, axitinib (AG-13736), AZD-0530, AZD-2171, bacillusCalmette-Guerin (BCG), bevacizumab (Avastin), BIO-117, BIO-145,BMS-184476, BMS-275183, BMS-528664, bortezomib (Velcade), C-1311(Symadex), cantuzumab mertansine, capecitabine (Xeloda), cetuximab(Erbitux), clofarabine (Clofarex), CMD-193, combretastatin, Cotara,CT-2106, CV-247, decitabine (Dacogen), E-7070, E-7820, edotecarin,EMD-273066, enzastaurin (LY-317615) epothilone B (EPO-906), erlotinib(Tarceva), flavopyridol, GCAN-101, gefitinib (Iressa), huA33,huC242-DM4, imatinib (Gleevec), indisulam, ING-1, irinotecan (CPT-11,Camptosar) ISIS 2503, ixabepilone, lapatinib (Tykerb), mapatumumab(HGS-ETR1), MBT-0206, MEDI-522 (Abregrin), Mitomycin, MK-0457 (VX-680),MLN-8054, NB-1011, NGR-TNF, NV-1020, oblimersen (Genasense, G3139),OncoVex, ONYX 015 (CI-1042), oxaliplatin (Eloxatin), panitumumab(ABX-EGF, Vectibix), pelitinib (EKB-569), pemetrexed (Alimta),PD-325901, PF-0337210, PF-2341066, RAD-001 (Everolimus), RAV-12,Resveratrol, Rexin-G, S-1 (TS-1), seliciclib, SN-38 liposome, Sodiumstibogluconate (SSG), sorafenib (Nexavar), SU-14813, sunitinib (Sutent),temsirolimus (CCI 779), tetrathiomolybdate, thalomide, TLK-286(Telcyta), topotecan (Hycamtin), trabectedin (Yondelis), vatalanib(PTK-787), vorinostat (SAHA, Zolinza), WX-UK1, and ZYC300, wherein theamounts of the active agent together with the amounts of the combinationanticancer agents are effective in treating colorectal cancer.

Some embodiments provide methods for the treatment of renal cellcarcinoma in a human in need of such treatment, comprising administeringto said human an amount of pharmaceutical compositions provided hereinin combination with one or more (preferably one to three) anti-canceragents selected from the group consisting of capecitabine (Xeloda),interferon alpha, interleukin-2, bevacizumab (Avastin), gemcitabine(Gemzar), thalidomide, cetuximab (Erbitux), vatalanib (PTK-787), Sutent,AG-13736, SU-11248, Tarceva, Iressa, Lapatinib and Gleevec, wherein theamounts of the active agent together with the amounts of the combinationanticancer agents is effective in treating renal cell carcinoma.

Some embodiments provide methods for the treatment of melanoma in ahuman in need of such treatment, comprising administering to said humanan amount of pharmaceutical compositions provided herein, in combinationwith one or more (preferably one to three) anti-cancer agents selectedfrom the group consisting of interferon alpha, interleukin-2,temozolomide (Temodar), docetaxel (Taxotere), paclitaxel, Dacarbazine(DTIC), carmustine (also known as BCNU), Cisplatin, vinblastine,tamoxifen, PD-325,901, Axitinib, bevacizumab (Avastin), thalidomide,sorafanib, vatalanib (PTK-787), Sutent, CpG-7909, AG-13736, Iressa,Lapatinib and Gleevec, wherein the amounts of the pharmaceuticalcompositions provided herein together with the amounts of thecombination anticancer agents is effective in treating melanoma.

Some embodiments provide methods for the treatment of lung cancer in ahuman in need of such treatment, comprising administering to said humanan amount of one or more pharmaceutical compositions provided herein incombination with one or more (preferably one to three) anti-canceragents selected from the group consisting of capecitabine (Xeloda),bevacizumab (Avastin), gemcitabine (Gemzar), docetaxel (Taxotere),paclitaxel, premetrexed disodium (Alimta), Tarceva, Iressa, Vinorelbine,Irinotecan, Etoposide, Vinblastine, and Paraplatin (carboplatin),wherein the amounts of the active agent together with the amounts of thecombination anticancer agents is effective in treating lung cancer.

The presence of at least one genetic alteration in at least one targetgene in a cancer subject, wherein the at least one target gene isselected from ALK1, BDNF, NGF, NGFR, NTF3, NTF4, ROS1, SORT1, NTRK1,NTRK2, and NTRK3 may be detected by use of an assay that includes one ormore antibodies that bind to at least two, three, four, or all of ALK,ROS1, TrkA, TrkB and TrkC biomarkers. The one or more molecularalterations detected in the biological sample may involve at least two,at least three, or at least four of the biomarkers. The knowledge of thepresence of the one or more molecular alterations in the biologicalsample may be acquired from an assay that includes contacting thebiological sample with one or more antibodies or fragments thereof thatare specific for the biomarkers. In some instances, the specificantibodies are monoclonal antibodies. In some instances, the specificantibodies include at least one of D5F3®, D4D5®, C17F1®, andcombinations thereof. In some instances, the biological sample iscontacted with one or more of the specific antibodies simultaneously. Insome instances, the biological sample is sequentially contacted with thespecific antibodies. In some instances, the one or more molecularalterations results in elevated expression of one or more of the ALK,ROS1, TrkA, TrkB, and TrkC biomarkers. In some instances, the knowledgeof the one or more molecular alterations is acquired from an assaywherein determining whether the expression of one or more biomarker iselevated includes: (a) determining the expression level of the one ormore biomarkers in the biological sample; and (b) comparing thedetermined expression level to a reference expression level.

As used herein, the term “reference level” refers to known expressionlevel of the target biomarker(s) in a control person or subject. In someinstances, the reference expression level is the expression level of thetarget biomarker(s) in a healthy person or subject. In some instances,the reference expression level is the expression level of the targetbiomarker(s) in a population of healthy control cells. In someinstances, the reference expression level is the expression level of thetarget biomarker(s) in a control person or subject that has beenpreviously determined to possess one or more molecular alterations. Insome instances, the reference expression level is the expression levelof the target biomarker(s) in a population of control cells that havebeen previously determined to possess one or more molecular alterations.

In some instances, the knowledge of the one or more molecularalterations is acquired from an antibody-based assay. The antibody-basedassay can generally be any antibody-based assay, and can be, forexample, ELISA, immunohistochemistry, western blotting, massspectrometry, flow cytometry, protein-microarray, immunofluorescence,and a multiplex detection assay. In some instances, the antibody-basedassay includes an immunohistochemistry analysis.

In some instances, identifying a ALK, ROS1, TrkA, TrkB, or TrkCmodulation defect such as an upregulation defect or a down-regulationdefect, for example a null mutation such as a ALK, ROS1, TrkA, TrkB, orTrkC deletion or a ALK, ROS1, TrkA, TrkB, or TrkC chimeric locusencoding a constitutively active ALK, ROS1, TrkA, TrkB, or TrkC kinasein a cancer or precancerous pancreatic cell in an subject comprisesassaying for ALK, ROS1, TrkA, TrkB, or TrkC activity in a cell extractfrom a pancreatic cancerous or precancerous cell population. In someinstances, identifying a ALK, ROS1, TrkA, TrkB, or TrkC modulationdefect such as an upregulation defect or a down-regulation defect, forexample a null mutation such as a ALK, ROS1, TrkA, TrkB, or TrkCdeletion or a ALK, ROS1, TrkA, TrkB, or TrkC chimeric locus encoding aconstitutively active ALK, ROS1, TrkA, TrkB, or TrkC kinase in a canceror precancerous pancreatic cell in an subject comprises assaying forALK, ROS1, TrkA, TrkB, or TrkC transcript accumulation in an RNApopulation from a pancreatic cancerous or precancerous cell population.In some instances, identifying a ALK, ROS1, TrkA, TrkB, or TrkCmodulation defect such as an upregulation defect or a down-regulationdefect, for example a null mutation such as a ALK, ROS1, TrkA, TrkB, orTrkC deletion or a ALK, ROS1, TrkA, TrkB, or TrkC chimeric locusencoding a constitutively active ALK, ROS1, TrkA, TrkB, or TrkC kinasein a cancer or precancerous pancreatic cell in an subject comprisesdetermining the nucleic acid sequence such as the genomicdeoxyribonucleic acid sequence in a cell or cells or a cell populationcomprising a cell or cells from a pancreatic cancerous or precancerouscell population.

The term “microarray,” as used herein, means an ordered arrangement ofarray elements (for example, small samples of a biological sample from asubject such as tissue samples) mounted on a solid support capable ofbinding other molecule species or antibodies. The array elements arearranged so that there are preferably at least one or more differentarray elements.

The term “solid support,” as used herein, means the well-understoodsolid materials to which various components such as, for example,proteins and nucleic acids, are physically attached, therebyimmobilizing the components. The term “solid support,” as used herein,means a non-liquid substance. A solid support can be, but is not limitedto, a membrane, sheet, gel, glass, plastic or metal. Immobilizedcomponents may be associated with a solid support by covalent bondsand/or via non-covalent attractive forces such as hydrogen bondinteractions, hydrophobic attractive forces and ionic forces, forexample.

In some instances, the microarrays suitable for the methods providedherein have a density of at least 1, 2, 4, 6, 8, 10 spots/cm²,preferably at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120,130, 140, 150, 160, 170, 180, 190, 200, more preferably at least 210,220, 230, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550,600, 650, 700, 750, 800, 850, 900, 950, 1000, 2000, 3000, 4000, 5000,6000, 7000, 8000 or 9000 spots/cm².

In some instances, it is contemplated that the spots on the array mayeach represent a different species of biomarkers or that the multiplespots on the array may represent the same species of biomarkers. In someinstances, the spots each represent an array element of differingidentity or characteristics.

In some instances, implementations of the methods according to this andother aspects of the present disclosure further include acquiringknowledge of a genetic alteration in the cancer of the subject from asecond analytical assay prior to the administering step. The secondanalytical assay can generally be any analytical assay known to thosehaving ordinary skill in the art, and can be for example anantibody-based assay, a nucleotide-based assay, or an enzymatic activityassay. Non-limiting examples of suitable second analytical assaysinclude capillary electrophoresis, nucleic acid sequencing, polypeptidesequencing, restriction digestion, nucleic acid amplification-basedassays, nucleic acid hybridization assay, comparative genomichybridization, real-time PCR, quantitative reverse transcription PCR(qRT-PCR), PCR-RFLP assay, HPLC, mass-spectrometric genotyping,fluorescent in-situ hybridization (FISH), next generation sequencing(NGS), and a kinase activity assay. Other examples of suitable secondanalytical assays include ELISA, immunohistochemistry, Western blotting,mass spectrometry, flow cytometry, protein-microarray,immunofluorescence, and multiplex detection assay.

In some instances, FISH analysis is used to identify the chromosomalrearrangement resulting in the one or more molecular alterations such asthe fusion genes or gene products as described herein. For example, toperform FISH, at least a first probe tagged with a first detectablelabel can be designed to target a first gene of a fusion gene, such asin one or more exons of the gene and at least a second probe tagged witha second detectable label can be designed to target a second gene of thefusion gene, such as in one or more exons of the genes (for example, theexons containing the part of the protein that includes the tyrosinekinase domain). The at least one first probe and the at least one secondprobe will be closer together in a subject who carries the fusioncompared to a subject who does not carry the fusion gene or geneproduct. In some instances, a variation of a FISH assay, for example,“break-apart FISH”, is used to evaluate a subject selected by a methodprovided herein. By this method, at least one probe targeting the fusionjunction and at least one probe targeting a subject gene of the fusion,e.g., at one or more exons and or introns of the gene, are utilized. Innormal cells, both probes will be observed (or a secondary color will beobserved due to the close proximity of the two genes of the genefusion), and only the single gene probe will be observed when thetranslocation occurs or the probes, having differing colors, will beseparated such that one of ordinary skill in the art observing theprobes can determine that a relevant gene fusion or deletion is presentin the sample. Generally, FISH assays are performed usingformalin-fixed, paraffin-embedded tissue sections that are placed onslides. The DNA from the tissue sample sections is denatured tosingle-stranded form and subsequently allowed to hybridize with theappropriate DNA probes that can be designed and prepared using methodsand techniques known to those having ordinary skill in the art.Following hybridization, any unbound probe may be removed by a series ofwashes and the nuclei of the cells are counter-stained with DAPI (4′,6diamidino-2-phenylindole), a DNA-specific stain that fluoresces blue.Hybridization of the probe or probes are viewed using a fluorescencemicroscope equipped with appropriate excitation and emission filters,allowing visualization of the fluorescent signals.

For example, a break-apart FISH assay may be used to detect multipletypes of rearrangements involving the ALK gene locus. In the method,tumor cells from some subjects having non-small cell lung cancer(NSCLC), display an ALK-positive FISH pattern as detected using singleinterference filter sets comprising green (FITC), red (Texas red), andblue (4′,6-diamidino-2-phenylindole) as well as dual (red/green) andtriple (blue, red, green) band-pass filters. A fusion of the ALK gene isvisualized as split orange and green signals, single orange signals, orsingle orange and single green signals.

Relevant molecular alterations with respect to ROS1, TrkA, TrkB and TrkCin biological samples derived from cancer subjects using the samemethods as described above, but by modifying the reagents, probes andother materials used in the assays in ways that are appropriate to thetarget molecular alteration and as can be readily determined by thosehaving ordinary skill in the art.

Other variations of the FISH method known in the art are suitable forevaluating a subject selected in accordance with the methods providedherein.

In some instances of the methods provided herein, the cancer is selectedfrom the group consisting of anaplastic large-cell lymphoma (ALCL),colorectal cancer (CRC), cholangiocarcinoma, gastric, glioblastomas(GBM), leiomyosarcoma, melanoma, non-small cell lung cancer (NSCLC),squamous cell lung cancer, neuroblastoma (NB), ovarian cancer,pancreatic cancer, prostate cancer, medullary thyroid cancer, breastcancer, and papillary thyroid cancer. In some instances are providedsuch methods, wherein the knowledge of the presence of the one or moremolecular alterations is obtained from an assay performed simultaneouslyon a plurality of biological samples. In some instances, the pluralityof biological samples may be assayed in a multitest platform.

As used herein, the term “multitest platform” is intended to encompassany suitable means to contain one or more reaction mixtures,suspensions, or detection reactions. As such, the outcomes of a numberof screening events can be assembled onto one surface, resulting in a“multitest platform” having, or consisting of multiple elements or partsto do more than one experiment simultaneously. It is intended that theterm “multitest platform” encompasses protein chips, microtiter plates,multi-well plates, microcards, test tubes, petri plates, trays, slides,and the like. In some instances, multiplexing can further includesimultaneously conducting a plurality of screening events in each of aplurality of separate biological samples. For example, the number ofbiological samples analyzed can be based on the number of spots on aslide and the number of tests conducted in each spot (as described ingreater detail in Example 2). In another example, the number ofbiological samples analyzed can be based on the number of wells in amulti-well plate and the number of tests conducted in each well. Forexample, 6-well, 12-well, 24-well, 48-well, 96-well, 384-well, 1536-wellor 3456-well microtiter plates can be useful in the presently disclosedmethods, although it will be appreciated by those in the art, not eachmicrotiter well need contain a subject biological sample. Depending onthe size of the microtiter plate and the number of the subjectbiological samples in each well, very high numbers of tests can be runsimultaneously. Although multiplexing has been exemplified in Example 2with respect to micro-slides, it will be understood that other formatscan be used for multiplexing.

In some instances are provided such methods, wherein the plurality ofbiological samples includes at least 6, 12, 24, 48, 96, 200, 384, 400,500, 1000, 1250, 1500, or 3000 samples.

In some instances are provided such methods, wherein the one or moremolecular alterations is selected from a genetic mutation, a geneamplification, a gene rearrangement, a single-nucleotide variation(SNV), a deletion, an insertion, an InDel mutation, a single nucleotidepoint mutation (SNP), an epigenetic alteration, a splicing variant, anRNA/protein overexpression, and an aberrant RNA/protein expression. Insome instances are provided such methods, wherein the genetic alterationincludes an insertion of a heterologous nucleic acid sequence within acoding sequence of a biomarker gene. In some instances are provided suchmethods, wherein the insertion forms a chimeric nucleic acid sequencethat encodes a fusion peptide.

In some instances are provided such methods, wherein the acquiringknowledge of the one or more molecular alterations further comprisesdetermining a nucleic acid sequence and/or an amino acid sequencecomprising the one or more molecular alterations. In some instances, thenucleic acid sequence comprising the one or more molecular alterationsfrom a selected cancer subject tumor is sequenced. In some instances,the sequence is determined by a next generation sequencing method.

Some embodiments provide a pharmaceutical composition comprising atherapeutically effective amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidein combination with one or more chemotherapeutic agents or radiotherapy,such as radiotherapy as commonly administered to treat, ameliorate thesymptoms of, or prevent or delay the onset of cancer. Such agents caninclude, but are not limited to, antihormonal agents such asantiestrogens, antiandrogens and aromatase inhibitors, topoisomerase Iinhibitors, topoisomerase II inhibitors, agents that targetmicrotubules, platin-based agents, alkylating agents, DNA damaging orintercalating agents, antineoplastic antimetabolites, other kinaseinhibitors, other anti-angiogenic agents, inhibitors of kinesins,therapeutic monoclonal antibodies, inhibitors of mTOR, histonedeacetylase inhibitors, farnesyl transferase inhibitors, and inhibitorsof hypoxic response.

Some embodiments provide a product or kit comprising a pharmaceuticalcomposition as provided herein comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideand one or more chemotherapeutic agents, as a combined preparation forsimultaneous, separate or sequential use in anticancer therapy.

Some embodiments include any of the methods described herein, whereinsaid cancer is selected from non-small cell lung cancer, papillarythyroid cancer, neuroblastoma, pancreatic cancer and colorectal cancer.Some embodiments are any of the methods described herein wherein saidcancer is non-small cell lung cancer. Some embodiments include any ofthe methods described herein, wherein said cancer is said cancer ispapillary thyroid cancer. Some embodiments include any of the methodsdescribed herein, wherein said cancer is wherein said cancer isneuroblastoma. Some embodiments include any of the methods describedherein, wherein said cancer is wherein said cancer is pancreatic cancer.

Some embodiments include any of the methods described herein, whereinsaid cancer is wherein said cancer is colorectal cancer.

Some embodiments relate to any of the pharmaceutical compositionsprovided herein for use as a medicament. Some embodiments relate to theuse of any of the pharmaceutical compositions provided herein for themanufacture of a medicament for the treatment of abnormal cell growth.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state at a total dose of about 600mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the T_(max)of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 2 hours and about 5hours, or between about 2.5 hours and about 4.7 hours, or between about2.4 hours and about 4.7 hours, or between about 2.6 hours and about 4.8hours, following said administration of said pharmaceutical compositionto said subject. In some embodiments, the at least one acidulant is anorganic acidulant. In some embodiments, the at least one acidulant isselected from tartaric acid, maleic acid, fumaric acid, citric acid, andbetaine hydrochloride. In some embodiments, the least one acidulant isfumaric acid. In some embodiments, the at least one acidulant istartaric acid. In some embodiments, the said at least one acidulant ismaleic acid. In some embodiments, the said at least one acidulant iscitric acid. In some embodiments, the said at least one acidulant isbetaine hydrochloride.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject at a total dose of about 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the T_(max)of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 2 hours and about 5hours, or between about 2.5 hours and about 4.7 hours, or between about2.4 hours and about 4.7 hours, or between about 2.6 hours and about 4.8hours, following said administration of said pharmaceutical compositionto said subject. In some embodiments, the at least one acidulant is anorganic acidulant. In some embodiments, the at least one acidulant isselected from tartaric acid, maleic acid, fumaric acid, citric acid, andbetaine hydrochloride. In some embodiments, the least one acidulant isfumaric acid. In some embodiments, the at least one acidulant istartaric acid. In some embodiments, the said at least one acidulant ismaleic acid. In some embodiments, the said at least one acidulant iscitric acid. In some embodiments, the said at least one acidulant isbetaine hydrochloride.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fed state at a total dose of about 600 mgof saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the T_(max)of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 4 hours and about 8hours, or between about 4.6 hours and about 5.4 hours, or between about4.5 hours and about 7.2 hours, or between about 4.2 hours and about 6.7hours, following said administration of said pharmaceutical compositionto said subject. In some embodiments, the at least one acidulant is anorganic acidulant. In some embodiments, the at least one acidulant isselected from tartaric acid, maleic acid, fumaric acid, citric acid, andbetaine hydrochloride. In some embodiments, the least one acidulant isfumaric acid. In some embodiments, the at least one acidulant istartaric acid. In some embodiments, the said at least one acidulant ismaleic acid. In some embodiments, the said at least one acidulant iscitric acid. In some embodiments, the said at least one acidulant isbetaine hydrochloride.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject at a total dose of about 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the T_(max)of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 4 hours and about 8hours, or between about 4.6 hours and about 5.4 hours, or between about4.5 hours and about 7.2 hours, or between about 4.2 hours and about 6.7hours, following said administration of said pharmaceutical compositionto said subject. In some embodiments, the at least one acidulant is anorganic acidulant. In some embodiments, the at least one acidulant isselected from tartaric acid, maleic acid, fumaric acid, citric acid, andbetaine hydrochloride. In some embodiments, the least one acidulant isfumaric acid. In some embodiments, the at least one acidulant istartaric acid. In some embodiments, the said at least one acidulant ismaleic acid. In some embodiments, the said at least one acidulant iscitric acid. In some embodiments, the said at least one acidulant isbetaine hydrochloride.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state at a total dose of about 600mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the C_(max)of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 1200 nM and about 3500nM, or between about 1500 nM and about 2800 nM, or between about 1490 nMand about 3030 nM, or between about 1670 nM and about 2930 nM, followingsaid administration of said pharmaceutical composition to said subject.In some embodiments, the at least one acidulant is an organic acidulant.In some embodiments, the at least one acidulant is selected fromtartaric acid, maleic acid, fumaric acid, citric acid, and betainehydrochloride. In some embodiments, the least one acidulant is fumaricacid. In some embodiments, the at least one acidulant is tartaric acid.In some embodiments, the said at least one acidulant is maleic acid. Insome embodiments, the said at least one acidulant is citric acid. Insome embodiments, the said at least one acidulant is betainehydrochloride.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject at a total dose of about 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the C_(max)of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 1200 nM and about 3500nM, or between about 1500 nM and about 2800 nM, or between about 1490 nMand about 3030 nM, or between about 1670 nM and about 2930 nM, followingsaid administration of said pharmaceutical composition to said subject.In some embodiments, the at least one acidulant is an organic acidulant.In some embodiments, the at least one acidulant is selected fromtartaric acid, maleic acid, fumaric acid, citric acid, and betainehydrochloride. In some embodiments, the least one acidulant is fumaricacid. In some embodiments, the at least one acidulant is tartaric acid.In some embodiments, the said at least one acidulant is maleic acid. Insome embodiments, the said at least one acidulant is citric acid. Insome embodiments, the said at least one acidulant is betainehydrochloride.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fed state at a total dose of about 600 mgof saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the C_(max)of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 1500 nM and about 3500nM, or between about 1810 nM and about 3070 nM, or between about 2210 nMand about 2990 nM, or between about 1990 nM and about 2810 nM, followingsaid administration of said pharmaceutical composition to said subject.In some embodiments, the at least one acidulant is an organic acidulant.In some embodiments, the at least one acidulant is selected fromtartaric acid, maleic acid, fumaric acid, citric acid, and betainehydrochloride. In some embodiments, the least one acidulant is fumaricacid. In some embodiments, the at least one acidulant is tartaric acid.In some embodiments, the said at least one acidulant is maleic acid. Insome embodiments, the said at least one acidulant is citric acid. Insome embodiments, the said at least one acidulant is betainehydrochloride.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject at a total dose of about 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the C_(max)of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 1500 nM and about 3500nM, or between about 1810 nM and about 3070 nM, or between about 2210 nMand about 2990 nM, or between about 1990 nM and about 2810 nM, followingsaid administration of said pharmaceutical composition to said subject.In some embodiments, the at least one acidulant is an organic acidulant.In some embodiments, the at least one acidulant is selected fromtartaric acid, maleic acid, fumaric acid, citric acid, and betainehydrochloride. In some embodiments, the least one acidulant is fumaricacid. In some embodiments, the at least one acidulant is tartaric acid.In some embodiments, the said at least one acidulant is maleic acid. Insome embodiments, the said at least one acidulant is citric acid. Insome embodiments, the said at least one acidulant is betainehydrochloride.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state at a total dose of about 600mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the AUC(0 to120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 30,000 nM*hr and about85,000 nM*hr, or between about 34,100 nM*hr and about 71,700 nM*hr, orbetween about 32,500 nM*hr and about 79,700 nM*hr, or between about37,100 nM*hr and about 77,300 nM*hr, following said administration ofsaid pharmaceutical composition to said subject. In some embodiments,the at least one acidulant is an organic acidulant. In some embodiments,the at least one acidulant is selected from tartaric acid, maleic acid,fumaric acid, citric acid, and betaine hydrochloride. In someembodiments, the least one acidulant is fumaric acid. In someembodiments, the at least one acidulant is tartaric acid. In someembodiments, the said at least one acidulant is maleic acid. In someembodiments, the said at least one acidulant is citric acid. In someembodiments, the said at least one acidulant is betaine hydrochloride.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject at a total dose of about 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the AUC(0 to120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 30,000 nM*hr and about85,000 nM*hr, or between about 34,100 nM*hr and about 71,700 nM*hr, orbetween about 32,500 nM*hr and about 79,700 nM*hr, or between about37,100 nM*hr and about 77,300 nM*hr, following said administration ofsaid pharmaceutical composition to said subject. In some embodiments,the at least one acidulant is an organic acidulant. In some embodiments,the at least one acidulant is selected from tartaric acid, maleic acid,fumaric acid, citric acid, and betaine hydrochloride. In someembodiments, the least one acidulant is fumaric acid. In someembodiments, the at least one acidulant is tartaric acid. In someembodiments, the said at least one acidulant is maleic acid. In someembodiments, the said at least one acidulant is citric acid. In someembodiments, the said at least one acidulant is betaine hydrochloride.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fed state at a total dose of about 600 mgof saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the AUC(0 to120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 35,000 nM*hr and about90,000 nM*hr, or between about 38,900 nM*hr and about 78,700 nM*hr, orbetween about 58,900 nM*hr and about 84,700 nM*hr, or between about51,300 nM*hr and about 77,500 nM*hr, following said administration ofsaid pharmaceutical composition to said subject. In some embodiments,the at least one acidulant is an organic acidulant. In some embodiments,the at least one acidulant is selected from tartaric acid, maleic acid,fumaric acid, citric acid, and betaine hydrochloride. In someembodiments, the least one acidulant is fumaric acid. In someembodiments, the at least one acidulant is tartaric acid. In someembodiments, the said at least one acidulant is maleic acid. In someembodiments, the said at least one acidulant is citric acid. In someembodiments, the said at least one acidulant is betaine hydrochloride.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject at a total dose of about 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the AUC(0 to120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 35,000 nM*hr and about90,000 nM*hr, or between about 38,900 nM*hr and about 78,700 nM*hr, orbetween about 58,900 nM*hr and about 84,700 nM*hr, or between about51,300 nM*hr and about 77,500 nM*hr, following said administration ofsaid pharmaceutical composition to said subject. In some embodiments,the at least one acidulant is an organic acidulant. In some embodiments,the at least one acidulant is selected from tartaric acid, maleic acid,fumaric acid, citric acid, and betaine hydrochloride. In someembodiments, the least one acidulant is fumaric acid. In someembodiments, the at least one acidulant is tartaric acid. In someembodiments, the said at least one acidulant is maleic acid. In someembodiments, the said at least one acidulant is citric acid. In someembodiments, the said at least one acidulant is betaine hydrochloride.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state at a total dose of about 600mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein theAUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 30,000 nM*hr and about85,000 nM*hr, or between about 34,700 nM*hr and about 72,900 nM*hr, orbetween about 33,200 nM*hr and about 81,200 nM*hr, or between about37,800 nM*hr and about 78,800 nM*hr, following said administration ofsaid pharmaceutical composition to said subject. In some embodiments,the at least one acidulant is an organic acidulant. In some embodiments,the at least one acidulant is selected from tartaric acid, maleic acid,fumaric acid, citric acid, and betaine hydrochloride. In someembodiments, the least one acidulant is fumaric acid. In someembodiments, the at least one acidulant is tartaric acid. In someembodiments, the said at least one acidulant is maleic acid. In someembodiments, the said at least one acidulant is citric acid. In someembodiments, the said at least one acidulant is betaine hydrochloride.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject at a total dose of about 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein theAUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 30,000 nM*hr and about85,000 nM*hr, or between about 34,700 nM*hr and about 72,900 nM*hr, orbetween about 33,200 nM*hr and about 81,200 nM*hr, or between about37,800 nM*hr and about 78,800 nM*hr, following said administration ofsaid pharmaceutical composition to said subject. In some embodiments,the at least one acidulant is an organic acidulant. In some embodiments,the at least one acidulant is selected from tartaric acid, maleic acid,fumaric acid, citric acid, and betaine hydrochloride. In someembodiments, the least one acidulant is fumaric acid. In someembodiments, the at least one acidulant is tartaric acid. In someembodiments, the said at least one acidulant is maleic acid. In someembodiments, the said at least one acidulant is citric acid. In someembodiments, the said at least one acidulant is betaine hydrochloride.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fed state at a total dose of about 600 mgof saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein theAUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 35,000 nM*hr and about90,000 nM*hr, or between about 39,100 nM*hr and about 79,700 nM*hr, orbetween about 59,400 nM*hr and about 87,200 nM*hr, or between about51,700 nM*hr and about 79,700 nM*hr, following said administration ofsaid pharmaceutical composition to said subject. In some embodiments,the at least one acidulant is an organic acidulant. In some embodiments,the at least one acidulant is selected from tartaric acid, maleic acid,fumaric acid, citric acid, and betaine hydrochloride. In someembodiments, the least one acidulant is fumaric acid. In someembodiments, the at least one acidulant is tartaric acid. In someembodiments, the said at least one acidulant is maleic acid. In someembodiments, the said at least one acidulant is citric acid. In someembodiments, the said at least one acidulant is betaine hydrochloride.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject at a total dose of about 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein theAUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 35,000 nM*hr and about90,000 nM*hr, or between about 39,100 nM*hr and about 79,700 nM*hr, orbetween about 59,400 nM*hr and about 87,200 nM*hr, or between about51,700 nM*hr and about 79,700 nM*hr, following said administration ofsaid pharmaceutical composition to said subject. In some embodiments,the at least one acidulant is an organic acidulant. In some embodiments,the at least one acidulant is selected from tartaric acid, maleic acid,fumaric acid, citric acid, and betaine hydrochloride. In someembodiments, the least one acidulant is fumaric acid. In someembodiments, the at least one acidulant is tartaric acid. In someembodiments, the said at least one acidulant is maleic acid. In someembodiments, the said at least one acidulant is citric acid. In someembodiments, the said at least one acidulant is betaine hydrochloride.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said acidulant is tartaric acid,wherein said pharmaceutical composition when administered to a subjectin a fasted state at a total dose of about 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the T_(max)of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 2 hours and about 5hours, or between about 2.5 hours and about 4.7 hours, or between about2.4 hours and about 4.7 hours, or between about 2.6 hours and about 4.8hours, following said administration of said pharmaceutical compositionto said subject.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said acidulant is tartaric acid,wherein said pharmaceutical composition when administered to a subjectat a total dose of about 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the T_(max)of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 2 hours and about 5hours, or between about 2.5 hours and about 4.7 hours, or between about2.4 hours and about 4.7 hours, or between about 2.6 hours and about 4.8hours, following said administration of said pharmaceutical compositionto said subject.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said acidulant is tartaric acid,wherein said pharmaceutical composition when administered to a subjectin a fed state at a total dose of about 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the T_(max)of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 4 hours and about 8hours, or between about 4.6 hours and about 5.4 hours, or between about4.5 hours and about 7.2 hours, or between about 4.2 hours and about 6.7hours, following said administration of said pharmaceutical compositionto said subject.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said acidulant is tartaric acid,wherein said pharmaceutical composition when administered to a subjectat a total dose of about 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the T_(max)of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 4 hours and about 8hours, or between about 4.6 hours and about 5.4 hours, or between about4.5 hours and about 7.2 hours, or between about 4.2 hours and about 6.7hours, following said administration of said pharmaceutical compositionto said subject.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said acidulant is tartaric acid,wherein said pharmaceutical composition when administered to a subjectin a fasted state at a total dose of about 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the C_(max)of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 1200 nM and about 3500nM, or between about 1500 nM and about 2800 nM, or between about 1490 nMand about 3030 nM, or between about 1670 nM and about 2930 nM, followingsaid administration of said pharmaceutical composition to said subject.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said acidulant is tartaric acid,wherein said pharmaceutical composition when administered to a subjectat a total dose of about 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the C_(max)of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 1200 nM and about 3500nM, or between about 1500 nM and about 2800 nM, or between about 1490 nMand about 3030 nM, or between about 1670 nM and about 2930 nM, followingsaid administration of said pharmaceutical composition to said subject.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said acidulant is tartaric acid,wherein said pharmaceutical composition when administered to a subjectin a fed state at a total dose of about 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the C_(max)of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 1500 nM and about 3500nM, or between about 1810 nM and about 3070 nM, or between about 2210 nMand about 2990 nM, or between about 1990 nM and about 2810 nM, followingsaid administration of said pharmaceutical composition to said subject.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said acidulant is tartaric acid,wherein said pharmaceutical composition when administered to a subjectat a total dose of about 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the C_(max)of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 1500 nM and about 3500nM, or between about 1810 nM and about 3070 nM, or between about 2210 nMand about 2990 nM, or between about 1990 nM and about 2810 nM, followingsaid administration of said pharmaceutical composition to said subject.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said acidulant is tartaric acid,wherein said pharmaceutical composition when administered to a subjectin a fasted state at a total dose of about 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the AUC(0 to120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 30,000 nM*hr and about85,000 nM*hr, or between about 34,100 nM*hr and about 71,700 nM*hr, orbetween about 32,500 nM*hr and about 79,700 nM*hr, or between about37,100 nM*hr and about 77,300 nM*hr, following said administration ofsaid pharmaceutical composition to said subject.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said acidulant is tartaric acid,wherein said pharmaceutical composition when administered to a subjectat a total dose of about 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the AUC(0 to120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 30,000 nM*hr and about85,000 nM*hr, or between about 34,100 nM*hr and about 71,700 nM*hr, orbetween about 32,500 nM*hr and about 79,700 nM*hr, or between about37,100 nM*hr and about 77,300 nM*hr, following said administration ofsaid pharmaceutical composition to said subject.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said acidulant is tartaric acid,wherein said pharmaceutical composition when administered to a subjectin a fed state at a total dose of about 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the AUC(0 to120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 35,000 nM*hr and about90,000 nM*hr, or between about 38,900 nM*hr and about 78,700 nM*hr, orbetween about 58,900 nM*hr and about 84,700 nM*hr, or between about51,300 nM*hr and about 77,500 nM*hr, following said administration ofsaid pharmaceutical composition to said subject.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said acidulant is tartaric acid,wherein said pharmaceutical composition when administered to a subjectat a total dose of about 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the AUC(0 to120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 35,000 nM*hr and about90,000 nM*hr, or between about 38,900 nM*hr and about 78,700 nM*hr, orbetween about 58,900 nM*hr and about 84,700 nM*hr, or between about51,300 nM*hr and about 77,500 nM*hr, following said administration ofsaid pharmaceutical composition to said subject.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said acidulant is tartaric acid,wherein said pharmaceutical composition when administered to a subjectin a fasted state at a total dose of about 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein theAUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 30,000 nM*hr and about85,000 nM*hr, or between about 34,700 nM*hr and about 72,900 nM*hr, orbetween about 33,200 nM*hr and about 81,200 nM*hr, or between about37,800 nM*hr and about 78,800 nM*hr, following said administration ofsaid pharmaceutical composition to said subject.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said acidulant is tartaric acid,wherein said pharmaceutical composition when administered to a subjectat a total dose of about 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein theAUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 30,000 nM*hr and about85,000 nM*hr, or between about 34,700 nM*hr and about 72,900 nM*hr, orbetween about 33,200 nM*hr and about 81,200 nM*hr, or between about37,800 nM*hr and about 78,800 nM*hr, following said administration ofsaid pharmaceutical composition to said subject.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said acidulant is tartaric acid,wherein said pharmaceutical composition when administered to a subjectin a fed state at a total dose of about 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein theAUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 35,000 nM*hr and about90,000 nM*hr, or between about 39,100 nM*hr and about 79,700 nM*hr, orbetween about 59,400 nM*hr and about 87,200 nM*hr, or between about51,700 nM*hr and about 79,700 nM*hr, following said administration ofsaid pharmaceutical composition to said subject.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said acidulant is tartaric acid,wherein said pharmaceutical composition when administered to a subjectat a total dose of about 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein theAUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 35,000 nM*hr and about90,000 nM*hr, or between about 39,100 nM*hr and about 79,700 nM*hr, orbetween about 59,400 nM*hr and about 87,200 nM*hr, or between about51,700 nM*hr and about 79,700 nM*hr, following said administration ofsaid pharmaceutical composition to said subject.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state at a total dose of about 600mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the T_(max)of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 2 hours and about 5hours, or between about 2.5 hours and about 4.7 hours, or between about2.4 hours and about 4.7 hours, or between about 2.6 hours and about 4.8hours, following said administration of said pharmaceutical compositionto said subject, wherein said pharmaceutical composition is in the formof a capsule. In some embodiments, the at least one acidulant is anorganic acidulant. In some embodiments, the at least one acidulant isselected from tartaric acid, maleic acid, fumaric acid, citric acid, andbetaine hydrochloride. In some embodiments, the least one acidulant isfumaric acid. In some embodiments, the at least one acidulant istartaric acid. In some embodiments, the said at least one acidulant ismaleic acid. In some embodiments, the said at least one acidulant iscitric acid. In some embodiments, the said at least one acidulant isbetaine hydrochloride.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject at a total dose of about 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the T_(max)of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 2 hours and about 5hours, or between about 2.5 hours and about 4.7 hours, or between about2.4 hours and about 4.7 hours, or between about 2.6 hours and about 4.8hours, following said administration of said pharmaceutical compositionto said subject, wherein said pharmaceutical composition is in the formof a capsule. In some embodiments, the at least one acidulant is anorganic acidulant. In some embodiments, the at least one acidulant isselected from tartaric acid, maleic acid, fumaric acid, citric acid, andbetaine hydrochloride. In some embodiments, the least one acidulant isfumaric acid. In some embodiments, the at least one acidulant istartaric acid. In some embodiments, the said at least one acidulant ismaleic acid. In some embodiments, the said at least one acidulant iscitric acid. In some embodiments, the said at least one acidulant isbetaine hydrochloride.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fed state at a total dose of about 600 mgof saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the T_(max)of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 4 hours and about 8hours, or between about 4.6 hours and about 5.4 hours, or between about4.5 hours and about 7.2 hours, or between about 4.2 hours and about 6.7hours, following said administration of said pharmaceutical compositionto said subject, wherein said pharmaceutical composition is in the formof a capsule. In some embodiments, the at least one acidulant is anorganic acidulant. In some embodiments, the at least one acidulant isselected from tartaric acid, maleic acid, fumaric acid, citric acid, andbetaine hydrochloride. In some embodiments, the least one acidulant isfumaric acid. In some embodiments, the at least one acidulant istartaric acid. In some embodiments, the said at least one acidulant ismaleic acid. In some embodiments, the said at least one acidulant iscitric acid. In some embodiments, the said at least one acidulant isbetaine hydrochloride.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject at a total dose of about 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the T_(max)of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 4 hours and about 8hours, or between about 4.6 hours and about 5.4 hours, or between about4.5 hours and about 7.2 hours, or between about 4.2 hours and about 6.7hours, following said administration of said pharmaceutical compositionto said subject, wherein said pharmaceutical composition is in the formof a capsule. In some embodiments, the at least one acidulant is anorganic acidulant. In some embodiments, the at least one acidulant isselected from tartaric acid, maleic acid, fumaric acid, citric acid, andbetaine hydrochloride. In some embodiments, the least one acidulant isfumaric acid. In some embodiments, the at least one acidulant istartaric acid. In some embodiments, the said at least one acidulant ismaleic acid. In some embodiments, the said at least one acidulant iscitric acid. In some embodiments, the said at least one acidulant isbetaine hydrochloride.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state at a total dose of about 600mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the C_(max)of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 1200 nM and about 3500nM, or between about 1500 nM and about 2800 nM, or between about 1490 nMand about 3030 nM, or between about 1670 nM and about 2930 nM, followingsaid administration of said pharmaceutical composition to said subject,wherein said pharmaceutical composition is in the form of a capsule. Insome embodiments, the at least one acidulant is an organic acidulant. Insome embodiments, the at least one acidulant is selected from tartaricacid, maleic acid, fumaric acid, citric acid, and betaine hydrochloride.In some embodiments, the least one acidulant is fumaric acid. In someembodiments, the at least one acidulant is tartaric acid. In someembodiments, the said at least one acidulant is maleic acid. In someembodiments, the said at least one acidulant is citric acid. In someembodiments, the said at least one acidulant is betaine hydrochloride.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject at a total dose of about 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the C_(max)of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 1200 nM and about 3500nM, or between about 1500 nM and about 2800 nM, or between about 1490 nMand about 3030 nM, or between about 1670 nM and about 2930 nM, followingsaid administration of said pharmaceutical composition to said subject,wherein said pharmaceutical composition is in the form of a capsule. Insome embodiments, the at least one acidulant is an organic acidulant. Insome embodiments, the at least one acidulant is selected from tartaricacid, maleic acid, fumaric acid, citric acid, and betaine hydrochloride.In some embodiments, the least one acidulant is fumaric acid. In someembodiments, the at least one acidulant is tartaric acid. In someembodiments, the said at least one acidulant is maleic acid. In someembodiments, the said at least one acidulant is citric acid. In someembodiments, the said at least one acidulant is betaine hydrochloride.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fed state at a total dose of about 600 mgof saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the C_(max)of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 1500 nM and about 3500nM, or between about 1810 nM and about 3070 nM, or between about 2210 nMand about 2990 nM, or between about 1990 nM and about 2810 nM, followingsaid administration of said pharmaceutical composition to said subject,wherein said pharmaceutical composition is in the form of a capsule. Insome embodiments, the at least one acidulant is an organic acidulant. Insome embodiments, the at least one acidulant is selected from tartaricacid, maleic acid, fumaric acid, citric acid, and betaine hydrochloride.In some embodiments, the least one acidulant is fumaric acid. In someembodiments, the at least one acidulant is tartaric acid. In someembodiments, the said at least one acidulant is maleic acid. In someembodiments, the said at least one acidulant is citric acid. In someembodiments, the said at least one acidulant is betaine hydrochloride.

In some embodiments are provided pharmaceutical compositions comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject at a total dose of about 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the C_(max)of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 1500 nM and about 3500nM, or between about 1810 nM and about 3070 nM, or between about 2210 nMand about 2990 nM, or between about 1990 nM and about 2810 nM, followingsaid administration of said pharmaceutical composition to said subject,wherein said pharmaceutical composition is in the form of a capsule. Insome embodiments, the at least one acidulant is an organic acidulant. Insome embodiments, the at least one acidulant is selected from tartaricacid, maleic acid, fumaric acid, citric acid, and betaine hydrochloride.In some embodiments, the least one acidulant is fumaric acid. In someembodiments, the at least one acidulant is tartaric acid. In someembodiments, the said at least one acidulant is maleic acid. In someembodiments, the said at least one acidulant is citric acid. In someembodiments, the said at least one acidulant is betaine hydrochloride.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state at a total dose of about 600mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the AUC(0 to120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 30,000 nM*hr and about85,000 nM*hr, or between about 34,100 nM*hr and about 71,700 nM*hr, orbetween about 32,500 nM*hr and about 79,700 nM*hr, or between about37,100 nM*hr and about 77,300 nM*hr, following said administration ofsaid pharmaceutical composition to said subject, wherein saidpharmaceutical composition is in the form of a capsule. In someembodiments, the at least one acidulant is an organic acidulant. In someembodiments, the at least one acidulant is selected from tartaric acid,maleic acid, fumaric acid, citric acid, and betaine hydrochloride. Insome embodiments, the least one acidulant is fumaric acid. In someembodiments, the at least one acidulant is tartaric acid. In someembodiments, the said at least one acidulant is maleic acid. In someembodiments, the said at least one acidulant is citric acid. In someembodiments, the said at least one acidulant is betaine hydrochloride.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject at a total dose of about 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the AUC(0 to120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 30,000 nM*hr and about85,000 nM*hr, or between about 34,100 nM*hr and about 71,700 nM*hr, orbetween about 32,500 nM*hr and about 79,700 nM*hr, or between about37,100 nM*hr and about 77,300 nM*hr, following said administration ofsaid pharmaceutical composition to said subject, wherein saidpharmaceutical composition is in the form of a capsule. In someembodiments, the at least one acidulant is an organic acidulant. In someembodiments, the at least one acidulant is selected from tartaric acid,maleic acid, fumaric acid, citric acid, and betaine hydrochloride. Insome embodiments, the least one acidulant is fumaric acid. In someembodiments, the at least one acidulant is tartaric acid. In someembodiments, the said at least one acidulant is maleic acid. In someembodiments, the said at least one acidulant is citric acid. In someembodiments, the said at least one acidulant is betaine hydrochloride.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fed state at a total dose of about 600 mgof saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the AUC(0 to120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 35,000 nM*hr and about90,000 nM*hr, or between about 38,900 nM*hr and about 78,700 nM*hr, orbetween about 58,900 nM*hr and about 84,700 nM*hr, or between about51,300 nM*hr and about 77,500 nM*hr, following said administration ofsaid pharmaceutical composition to said subject, wherein saidpharmaceutical composition is in the form of a capsule. In someembodiments, the at least one acidulant is an organic acidulant. In someembodiments, the at least one acidulant is selected from tartaric acid,maleic acid, fumaric acid, citric acid, and betaine hydrochloride. Insome embodiments, the least one acidulant is fumaric acid. In someembodiments, the at least one acidulant is tartaric acid. In someembodiments, the said at least one acidulant is maleic acid. In someembodiments, the said at least one acidulant is citric acid. In someembodiments, the said at least one acidulant is betaine hydrochloride.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject at a total dose of about 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the AUC(0 to120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 35,000 nM*hr and about90,000 nM*hr, or between about 38,900 nM*hr and about 78,700 nM*hr, orbetween about 58,900 nM*hr and about 84,700 nM*hr, or between about51,300 nM*hr and about 77,500 nM*hr, following said administration ofsaid pharmaceutical composition to said subject, wherein saidpharmaceutical composition is in the form of a capsule. In someembodiments, the at least one acidulant is an organic acidulant. In someembodiments, the at least one acidulant is selected from tartaric acid,maleic acid, fumaric acid, citric acid, and betaine hydrochloride. Insome embodiments, the least one acidulant is fumaric acid. In someembodiments, the at least one acidulant is tartaric acid. In someembodiments, the said at least one acidulant is maleic acid. In someembodiments, the said at least one acidulant is citric acid. In someembodiments, the said at least one acidulant is betaine hydrochloride.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state at a total dose of about 600mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein theAUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 30,000 nM*hr and about85,000 nM*hr, or between about 34,700 nM*hr and about 72,900 nM*hr, orbetween about 33,200 nM*hr and about 81,200 nM*hr, or between about37,800 nM*hr and about 78,800 nM*hr, following said administration ofsaid pharmaceutical composition to said subject, wherein saidpharmaceutical composition is in the form of a capsule. In someembodiments, the at least one acidulant is an organic acidulant. In someembodiments, the at least one acidulant is selected from tartaric acid,maleic acid, fumaric acid, citric acid, and betaine hydrochloride. Insome embodiments, the least one acidulant is fumaric acid. In someembodiments, the at least one acidulant is tartaric acid. In someembodiments, the said at least one acidulant is maleic acid. In someembodiments, the said at least one acidulant is citric acid. In someembodiments, the said at least one acidulant is betaine hydrochloride.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject at a total dose of about 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein theAUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 30,000 nM*hr and about85,000 nM*hr, or between about 34,700 nM*hr and about 72,900 nM*hr, orbetween about 33,200 nM*hr and about 81,200 nM*hr, or between about37,800 nM*hr and about 78,800 nM*hr, following said administration ofsaid pharmaceutical composition to said subject, wherein saidpharmaceutical composition is in the form of a capsule. In someembodiments, the at least one acidulant is an organic acidulant. In someembodiments, the at least one acidulant is selected from tartaric acid,maleic acid, fumaric acid, citric acid, and betaine hydrochloride. Insome embodiments, the least one acidulant is fumaric acid. In someembodiments, the at least one acidulant is tartaric acid. In someembodiments, the said at least one acidulant is maleic acid. In someembodiments, the said at least one acidulant is citric acid. In someembodiments, the said at least one acidulant is betaine hydrochloride.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fed state at a total dose of about 600 mgof saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein theAUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 35,000 nM*hr and about90,000 nM*hr, or between about 39,100 nM*hr and about 79,700 nM*hr, orbetween about 59,400 nM*hr and about 87,200 nM*hr, or between about51,700 nM*hr and about 79,700 nM*hr, following said administration ofsaid pharmaceutical composition to said subject, wherein saidpharmaceutical composition is in the form of a capsule. In someembodiments, the at least one acidulant is an organic acidulant. In someembodiments, the at least one acidulant is selected from tartaric acid,maleic acid, fumaric acid, citric acid, and betaine hydrochloride. Insome embodiments, the least one acidulant is fumaric acid. In someembodiments, the at least one acidulant is tartaric acid. In someembodiments, the said at least one acidulant is maleic acid. In someembodiments, the said at least one acidulant is citric acid. In someembodiments, the said at least one acidulant is betaine hydrochloride.

In some embodiments are provided pharmaceutical compositions, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject at a total dose of about 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein theAUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 35,000 nM*hr and about90,000 nM*hr, or between about 39,100 nM*hr and about 79,700 nM*hr, orbetween about 59,400 nM*hr and about 87,200 nM*hr, or between about51,700 nM*hr and about 79,700 nM*hr, following said administration ofsaid pharmaceutical composition to said subject, wherein saidpharmaceutical composition is in the form of a capsule. In someembodiments, the at least one acidulant is an organic acidulant. In someembodiments, the at least one acidulant is selected from tartaric acid,maleic acid, fumaric acid, citric acid, and betaine hydrochloride. Insome embodiments, the least one acidulant is fumaric acid. In someembodiments, the at least one acidulant is tartaric acid. In someembodiments, the said at least one acidulant is maleic acid. In someembodiments, the said at least one acidulant is citric acid. In someembodiments, the said at least one acidulant is betaine hydrochloride.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering a T_(max) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 2 hours and about 5 hours,or between about 2.5 hours and about 4.7 hours, or between about 2.4hours and about 4.7 hours, or between about 2.6 hours and about 4.8hours, following administration of said pharmaceutical composition tosaid subject in a fasted state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering a T_(max) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 2 hours and about 5 hours,or between about 2.5 hours and about 4.7 hours, or between about 2.4hours and about 4.7 hours, or between about 2.6 hours and about 4.8hours, following administration of said pharmaceutical composition tosaid subject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering a T_(max) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 4 hours and about 8 hours,or between about 4.6 hours and about 5.4 hours, or between about 4.5hours and about 7.2 hours, or between about 4.2 hours and about 6.7hours, following administration of said pharmaceutical composition tosaid subject in a fed state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering a T_(max) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 4 hours and about 8 hours,or between about 4.6 hours and about 5.4 hours, or between about 4.5hours and about 7.2 hours, or between about 4.2 hours and about 6.7hours, following administration of said pharmaceutical composition tosaid subject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering a C_(max) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 1200 nM and about 3500 nM,or between about 1500 nM and about 2800 nM, or between about 1490 nM andabout 3030 nM, or between about 1670 nM and about 2930 nM, followingadministration of said pharmaceutical composition to said subject in afasted state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering a C_(max) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 1200 nM and about 3500 nM,or between about 1500 nM and about 2800 nM, or between about 1490 nM andabout 3030 nM, or between about 1670 nM and about 2930 nM, followingadministration of said pharmaceutical composition to said subject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering a C_(max) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 1500 nM and about 3500 nM,or between about 1810 nM and about 3070 nM, or between about 2210 nM andabout 2990 nM, or between about 1990 nM and about 2810 nM, followingadministration of said pharmaceutical composition to said subject in afed state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering a C_(max) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 1500 nM and about 3500 nM,or between about 1810 nM and about 3070 nM, or between about 2210 nM andabout 2990 nM, or between about 1990 nM and about 2810 nM, followingadministration of said pharmaceutical composition to said subject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(0 to 120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 30,000 nM*hr and about85,000 nM*hr, or between about 34,100 nM*hr and about 71,700 nM*hr, orbetween about 32,500 nM*hr and about 79,700 nM*hr, or between about37,100 nM*hr and about 77,300 nM*hr, following administration of saidpharmaceutical composition to said subject in a fasted state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(0 to 120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 30,000 nM*hr and about85,000 nM*hr, or between about 34,100 nM*hr and about 71,700 nM*hr, orbetween about 32,500 nM*hr and about 79,700 nM*hr, or between about37,100 nM*hr and about 77,300 nM*hr, following administration of saidpharmaceutical composition to said subject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(0 to 120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 35,000 nM*hr and about90,000 nM*hr, or between about 38,900 nM*hr and about 78,700 nM*hr, orbetween about 58,900 nM*hr and about 84,700 nM*hr, or between about51,300 nM*hr and about 77,500 nM*hr, following administration of saidpharmaceutical composition to said subject in a fed state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(0 to 120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 35,000 nM*hr and about90,000 nM*hr, or between about 38,900 nM*hr and about 78,700 nM*hr, orbetween about 58,900 nM*hr and about 84,700 nM*hr, or between about51,300 nM*hr and about 77,500 nM*hr, following administration of saidpharmaceutical composition to said subject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 30,000 nM*hr and about85,000 nM*hr, or between about 34,700 nM*hr and about 72,900 nM*hr, orbetween about 33,200 nM*hr and about 81,200 nM*hr, or between about37,800 nM*hr and about 78,800 nM*hr, following administration of saidpharmaceutical composition to said subject in a fasted state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 30,000 nM*hr and about85,000 nM*hr, or between about 34,700 nM*hr and about 72,900 nM*hr, orbetween about 33,200 nM*hr and about 81,200 nM*hr, or between about37,800 nM*hr and about 78,800 nM*hr, following administration of saidpharmaceutical composition to said subject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(0 to 120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 35,000 nM*hr and about90,000 nM*hr, or between about 39,100 nM*hr and about 79,700 nM*hr, orbetween about 59,400 nM*hr and about 87,200 nM*hr, or between about51,700 nM*hr and about 79,700 nM*hr, following administration of saidpharmaceutical composition to said subject in a fed state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(0 to 120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 35,000 nM*hr and about90,000 nM*hr, or between about 39,100 nM*hr and about 79,700 nM*hr, orbetween about 59,400 nM*hr and about 87,200 nM*hr, or between about51,700 nM*hr and about 79,700 nM*hr, following administration of saidpharmaceutical composition to said subject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering a Tmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 2 hours and about 5 hoursfollowing administration of said pharmaceutical composition to saidsubject in a fasted state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering a Tmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 2 hours and about 5 hoursfollowing administration of said pharmaceutical composition to saidsubject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering a Tmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 4 hours and about 6 hoursfollowing administration of said pharmaceutical composition to saidsubject in a fed state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering a Tmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 4 hours and about 6 hoursfollowing administration of said pharmaceutical composition to saidsubject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering a Tmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 4 hours and about 8 hoursfollowing administration of said pharmaceutical composition to saidsubject in a fed state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering a Tmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 4 hours and about 8 hoursfollowing administration of said pharmaceutical composition to saidsubject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering a Tmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 4 hours and about 7 hoursfollowing administration of said pharmaceutical composition to saidsubject in a fed state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering a Tmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 4 hours and about 7 hoursfollowing administration of said pharmaceutical composition to saidsubject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering a Cmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 1500 nM and about 2800 nMfollowing administration of said pharmaceutical composition to saidsubject in a fasted state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering a Cmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 1500 nM and about 2800 nMfollowing administration of said pharmaceutical composition to saidsubject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering a Cmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 1490 nM and about 3030 nMfollowing administration of said pharmaceutical composition to saidsubject in a fasted state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering a Cmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 1490 nM and about 3030 nMfollowing administration of said pharmaceutical composition to saidsubject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering a Cmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 1670 nM and about 2930 nMfollowing administration of said pharmaceutical composition to saidsubject in a fasted state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering a Cmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 1670 nM and about 2930 nMfollowing administration of said pharmaceutical composition to saidsubject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering a Cmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 1810 nM and about 3070 nMfollowing administration of said pharmaceutical composition to saidsubject in a fed state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering a Cmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 1810 nM and about 3070 nMfollowing administration of said pharmaceutical composition to saidsubject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering a Cmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 2210 nM and about 2990 nMfollowing administration of said pharmaceutical composition to saidsubject in a fed state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering a Cmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 2210 nM and about 2990 nMfollowing administration of said pharmaceutical composition to saidsubject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering a Cmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 1990 nM and about 2810 nMfollowing administration of said pharmaceutical composition to saidsubject in a fed state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering a Cmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 1990 nM and about 2810 nMfollowing administration of said pharmaceutical composition to saidsubject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(0 to 120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 34,100 nM*hr and about71,700 nM*hr following administration of said pharmaceutical compositionto said subject in a fasted state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(0 to 120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 34,100 nM*hr and about71,700 nM*hr following administration of said pharmaceutical compositionto said subject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(0 to 120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 32,500 nM*hr and about79,700 nM*hr following administration of said pharmaceutical compositionto said subject in a fasted state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(0 to 120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 32,500 nM*hr and about79,700 nM*hr following administration of said pharmaceutical compositionto said subject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(0 to 120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 37,100 nM*hr and about77,300 nM*hr following administration of said pharmaceutical compositionto said subject in a fasted state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(0 to 120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 37,100 nM*hr and about77,300 nM*hr following administration of said pharmaceutical compositionto said subject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(0 to 120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 38,900 nM*hr and about78,700 nM*hr following administration of said pharmaceutical compositionto said subject in a fed state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(0 to 120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 38,900 nM*hr and about78,700 nM*hr following administration of said pharmaceutical compositionto said subject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(0 to 120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 58,900 nM*hr and about84,700 nM*hr following administration of said pharmaceutical compositionto said subject in a fed state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(0 to 120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 58,900 nM*hr and about84,700 nM*hr following administration of said pharmaceutical compositionto said subject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(0 to 120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 51,300 nM*hr and about77,500 nM*hr following administration of said pharmaceutical compositionto said subject in a fed state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(0 to 120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 51,300 nM*hr and about77,500 nM*hr following administration of said pharmaceutical compositionto said subject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 34,700 nM*hr and about72,900 nM*hr following administration of said pharmaceutical compositionto said subject in a fasted state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 34,700 nM*hr and about72,900 nM*hr following administration of said pharmaceutical compositionto said subject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 33,200 nM*hr and about81,200 nM*hr following administration of said pharmaceutical compositionto said subject in a fasted state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 33,200 nM*hr and about81,200 nM*hr following administration of said pharmaceutical compositionto said subject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 37,800 nM*hr and about78,800 nM*hr following administration of said pharmaceutical compositionto said subject in a fasted state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 37,800 nM*hr and about78,800 nM*hr following administration of said pharmaceutical compositionto said subject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 39,100 nM*hr and about79,700 nM*hr following administration of said pharmaceutical compositionto said subject in a fed state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 39,100 nM*hr and about79,700 nM*hr following administration of said pharmaceutical compositionto said subject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 59,400 nM*hr and about87,200 nM*hr following administration of said pharmaceutical compositionto said subject in a fed state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 59,400 nM*hr and about87,200 nM*hr following administration of said pharmaceutical compositionto said subject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 51,700 nM*hr and about79,700 nM*hr following administration of said pharmaceutical compositionto said subject in a fed state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject of between about 51,700 nM*hr and about79,700 nM*hr following administration of said pharmaceutical compositionto said subject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an Tmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 3.6 hours,based on a 90 percent confidence interval, following administration ofsaid pharmaceutical composition to said subject in a fasted state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an Tmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 3.6 hours,based on a 90 percent confidence interval, following administration ofsaid pharmaceutical composition to said subject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an Tmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 3.5 hours,based on a 90 percent confidence interval, following administration ofsaid pharmaceutical composition to said subject in a fasted state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an Tmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 3.5 hours,based on a 90 percent confidence interval, following administration ofsaid pharmaceutical composition to said subject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an Tmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 3.7 hours,based on a 90 percent confidence interval, following administration ofsaid pharmaceutical composition to said subject in a fasted state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an Tmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 3.7 hours,based on a 90 percent confidence interval, following administration ofsaid pharmaceutical composition to said subject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an Tmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 5 hours, basedon a 90 percent confidence interval, following administration of saidpharmaceutical composition to said subject in a fed state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an Tmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 5 hours, basedon a 90 percent confidence interval, following administration of saidpharmaceutical composition to said subject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an Tmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 5.8 hours,based on a 90 percent confidence interval, following administration ofsaid pharmaceutical composition to said subject in a fed state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an Tmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 5.8 hours,based on a 90 percent confidence interval, following administration ofsaid pharmaceutical composition to said subject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an Tmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 5.4 hours,based on a 90 percent confidence interval, following administration ofsaid pharmaceutical composition to said subject in a fed state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an Tmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 5.4 hours,based on a 90 percent confidence interval, following administration ofsaid pharmaceutical composition to said subject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an Cmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 2150 nM, basedon a 90 percent confidence interval, following administration of saidpharmaceutical composition to said subject in a fasted state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an Cmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 2150 nM, basedon a 90 percent confidence interval, following administration of saidpharmaceutical composition to said subject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an Cmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 2260 nM, basedon a 90 percent confidence interval, following administration of saidpharmaceutical composition to said subject in a fasted state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an Cmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 2260 nM, basedon a 90 percent confidence interval, following administration of saidpharmaceutical composition to said subject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an Cmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 2300 nM, basedon a 90 percent confidence interval, following administration of saidpharmaceutical composition to said subject in a fasted state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[45-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an Cmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 2300 nM, basedon a 90 percent confidence interval, following administration of saidpharmaceutical composition to said subject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an Cmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 2440 nM, basedon a 90 percent confidence interval, following administration of saidpharmaceutical composition to said subject in a fed state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an Cmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 2440 nM, basedon a 90 percent confidence interval, following administration of saidpharmaceutical composition to said subject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an Cmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 2600 nM, basedon a 90 percent confidence interval, following administration of saidpharmaceutical composition to said subject in a fed state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an Cmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 2600 nM, basedon a 90 percent confidence interval, following administration of saidpharmaceutical composition to said subject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an Cmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 2400 nM, basedon a 90 percent confidence interval, following administration of saidpharmaceutical composition to said subject in a fed state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an Cmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 2400 nM, basedon a 90 percent confidence interval, following administration of saidpharmaceutical composition to said subject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(0 to 120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 52,900 nM*hr,based on a 90 percent confidence interval, following administration ofsaid pharmaceutical composition to said subject in a fasted state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(0 to 120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 52,900 nM*hr,based on a 90 percent confidence interval, following administration ofsaid pharmaceutical composition to said subject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(0 to 120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 56,100 nM*hr,based on a 90 percent confidence interval, following administration ofsaid pharmaceutical composition to said subject in a fasted state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(0 to 120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 56,100 nM*hr,based on a 90 percent confidence interval, following administration ofsaid pharmaceutical composition to said subject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(0 to 120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 57,200 nM*hr,based on a 90 percent confidence interval, following administration ofsaid pharmaceutical composition to said subject in a fasted state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(0 to 120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 57,200 nM*hr,based on a 90 percent confidence interval, following administration ofsaid pharmaceutical composition to said subject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(0 to 120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 58,800 nM*hr,based on a 90 percent confidence interval, following administration ofsaid pharmaceutical composition to said subject in a fed state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(0 to 120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 58,800 nM*hr,based on a 90 percent confidence interval, following administration ofsaid pharmaceutical composition to said subject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(0 to 120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 71,800 nM*hr,based on a 90 percent confidence interval, following administration ofsaid pharmaceutical composition to said subject in a fed state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(0 to 120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 71,800 nM*hr,based on a 90 percent confidence interval, following administration ofsaid pharmaceutical composition to said subject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(0 to 120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 64,400 nM*hr,based on a 90 percent confidence interval, following administration ofsaid pharmaceutical composition to said subject in a fed state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(0 to 120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 64,400 nM*hr,based on a 90 percent confidence interval, following administration ofsaid pharmaceutical composition to said subject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 53,800 nM*hr,based on a 90 percent confidence interval, following administration ofsaid pharmaceutical composition to said subject in a fasted state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 53,800 nM*hr,based on a 90 percent confidence interval, following administration ofsaid pharmaceutical composition to said subject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 57,200 nM*hr,based on a 90 percent confidence interval, following administration ofsaid pharmaceutical composition to said subject in a fasted state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 57,200 nM*hr,based on a 90 percent confidence interval, following administration ofsaid pharmaceutical composition to said subject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 58,300 nM*hr,based on a 90 percent confidence interval, following administration ofsaid pharmaceutical composition to said subject in a fasted state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 58,300 nM*hr,based on a 90 percent confidence interval, following administration ofsaid pharmaceutical composition to said subject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 59,400 nM*hr,based on a 90 percent confidence interval, following administration ofsaid pharmaceutical composition to said subject in a fed state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 59,400 nM*hr,based on a 90 percent confidence interval, following administration ofsaid pharmaceutical composition to said subject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 73,300 nM*hr,based on a 90 percent confidence interval, following administration ofsaid pharmaceutical composition to said subject in a fed state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 73,300 nM*hr,based on a 90 percent confidence interval, following administration ofsaid pharmaceutical composition to said subject.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 65,700 nM*hr,based on a 90 percent confidence interval, following administration ofsaid pharmaceutical composition to said subject in a fed state.

In some embodiments are provided pharmaceutical compositions, comprising(a)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;and (b) means for delivering an AUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of a subject that is between 80% to 125% of 65,700 nM*hr,based on a 90 percent confidence interval, following administration ofsaid pharmaceutical composition to said subject.

EXAMPLES

All numbers expressing quantities of ingredients, reaction conditions,and so forth used in the specification are to be understood as beingmodified in all instances by the term “about.” Accordingly, unlessindicated to the contrary, the numerical parameters set forth herein areapproximations that may vary depending upon the desired propertiessought to be obtained. At the very least, and not as an attempt to limitthe application of the doctrine of equivalents to the scope of anyclaims in any application claiming priority to the present application,each numerical parameter should be construed in light of the number ofsignificant digits and ordinary rounding approaches.

As will be understood by one skilled in the art, for any and allpurposes, such as in terms of providing a written description, allranges provided herein also encompass any and all possible sub-rangesand combinations of sub-ranges thereof. Any listed range can be easilyrecognized as sufficiently describing and enabling the same range beingbroken down into at least equal halves, thirds, quarters, fifths,tenths, etc. As a non-limiting example, each range discussed herein canbe readily broken down into a lower third, middle third and upper third,etc. As will also be understood by one skilled in the art all languagesuch as “up to,” “at least,” “greater than,” “less than,” and the likeinclude the number recited and refer to ranges which can be subsequentlybroken down into sub-ranges as discussed above. Finally, as will beunderstood by one skilled in the art, a range includes each subjectmember. Thus, for example, a group having 1-3 articles refers to groupshaving 1, 2, or 3 articles. Similarly, a group having 1-5 articlesrefers to groups having 1, 2, 3, 4, or 5 articles, and so forth.

Example 1

A pharmaceutical composition comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideand fumaric acid was prepared as follows.

Target Target weight Actual amount per per weight dosage unit batch perComponent (mg) % w/w (g) batch (g) N-[5-(3,5-difluorobenzyl)- 200.044.44 66.67 66.67 1H-indazol-3-yl]-4-(4- methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4- ylamino)-benzamide Fumaric acid 50.0 11.11 16.6716.67 Isomalt 173.0 38.44 57.67 57.67 Pregelatinized starch, NF 22.505.00 7.50 7.50 (Starch 1500) Colloidal silicon dioxide 2.25 0.50 0.750.7542 (Cab-O-Sil ®) Magnesium stearate, NF 2.25 0.50 0.75 0.75(HyQual ® 5712 Powder) Total 450.00 100.00 150.00 150.01

N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidewas milled and the resulting materials were passed through a 60-meshscreen. The specified amount of fumaric acid was ground using a mortarand pestle and the resulting materials were passed through a 60-meshscreen. The fumaric acid was added to a V-blender and was blended forabout 30 seconds, after which theN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidewas added to the blender and the resulting mixture was blended for aboutone minute at 25 rpm. About one-half of the isomalt (estimated bysight), the pregelatinized starch, and the colloidal silicon dioxidewere added to the blender and the resulting mixture was blended forabout 3 minutes. The remainder of the isomalt was added along with themagnesium stearate to a large weighing boat, the mixture was stirred.The resulting mixture of isomalt and magnesium stearate was then addedto the blender and the mixture was blended for about 3 minutes at 25rpm. The mixture was removed from the blender, screened through a40-mesh screen and placed into a plastic bag. Bisected, modified ovaltablets were prepared from the mixture using tooling with dimensions of0.3200×0.5800. Some sticking issues were observed with this tooling, soit was switched to tooling for a caplet having dimensions of 0.25×0.75,which resulted in tablets that were less susceptible to sticking.Tablets were then prepared by wiping the tooling with magnesium stearateon a swab after each tableting run. Generally, the flow of the powderprior to tableting was somewhat poor and it required stirring, butcompression of the tablets was acceptable when the tooling was wipedeach time with magnesium stearate.

Example 2

A pharmaceutical composition comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideand glycine hydrochloride was prepared as follows.

Target amount Target per weight dosage per Actual unit batch weight perComponent (mg) % w/w (g) batch (g) N-[5-(3,5-difluorobenzyl)-1H- 200.044.44 66.67 66.67 indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro- 2H-pyran-4-ylamino)- benzamide Glycinehydrochloride 48.00 10.67 16.00 16.00 Isomalt 175.0 38.89 58.33 58.33Pregelatinized starch, NF 22.50 5.00 7.50 7.50 (Starch 1500) Colloidalsilicon dioxide 2.25 0.50 0.75 0.7542 (Cab-O-Sil ®) Magnesium stearate,NF 2.25 0.50 0.75 0.75 (HyQual ® 5712 Powder) Total 450.00 100.00 150.00150.00

Glycine hydrochloride was ground in a mortar and pestle.N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidewas milled, but was not screened. Approximately the same volumes ofisomalt and magnesium stearate were added to a weighing boat and stirredtogether. Approximately the same volumes of isomalt and colloidalsilicon dioxide were added to a weighing boat. The mixture of isomaltand colloidal silicon dioxide were added to a plastic bag, along withthe remaining isomalt, pregelatinized starch, and glycine hydrochloride.The resulting mixture was mixed briefly in the plastic bag, after whichtime theN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidewas added to the plastic bag and the resulting mixture was mixed in theplastic bag by hand for about one minute. The resulting mixture in theplastic bag was screened through a 40-mesh screen and was added to aV-blender. The mixture of magnesium stearate and isomalt from theweighing boat were also added to the V-blender and the resulting mixturewas blended at about 25 rpm for about 10 minutes.

Tablets were prepared from the above mixture using tooling for capletshaving dimensions measuring 0.2500×0.7500. Sticking and capping occurredon the first two tablets. The tableting tooling was cleaned and swabbedwith magnesium stearate, but tablet sticking was still significant andthe weight of the resulting tablets varied significantly. The flow ofthe powder entering the tableting tooling was sensitive to the headspace in the hopper.

Example 3

A pharmaceutical composition comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideandbetaine hydrochloride was prepared as follows.

Target Actual Target weight weight amount per per per dosage unit batchbatch Component (mg) % w/w (g) (g) N-[5-(3,5-difluorobenzyl)-1H- 200.044.44 66.67 66.67 indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro- 2H-pyran-4-ylamino)- benzamide Betainehydrochloride 66.50 14.78 22.17 22.17 Isomalt 156.50 34.78 52.17 52.17Pregelatinized starch, NF 22.50 5.00 7.50 7.50 (Starch 1500) Colloidalsilicon dioxide 2.25 0.50 0.75 0.75 (Cab-O-Sil ®) Magnesium stearate, NF2.25 0.50 0.75 0.75 (HyQual ® 5712 Powder) Total 450.00 100.00 150.00150.00

The betaine hydrochloride was ground in a mortar and pestle before use.TheN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidewas milled before use. Approximately the same volumes of isomalt andmagnesium stearate were added to a weighing boat and stirred together.Approximately the same volumes of isomalt and colloidal silicon dioxidewere added to a weighing boat and stirred together in a plastic bag. Theremaining isomalt, pregelatinized starch and betaine hydrochloride wereadded to a plastic bag and briefly mixed together. All theN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidewas added to the plastic bag and the resulting mixture was mixed by handin the plastic bag for about one minute. The resulting mixture in theplastic bag was screened through a 40-mesh screen and was added to aV-blender. The mixture of magnesium stearate and isomalt from theweighing boat were also added to the V-blender and the resulting mixturewas blended at about 25 rpm for about 3 minutes.

Tablets were prepared from the above mixture using tooling for capletshaving dimensions measuring 0.2500×0.750. The flow of the powder in thehopper was improved and wiping of the tooling with magnesium stearatewas only infrequently required.

Example 4

A pharmaceutical composition comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideandbetaine hydrochloride was prepared as follows.

Actual Target weight amount per Target per dosage unit weight per batchComponent (mg) % w/w batch (g) (g) N-[5-(3,5-difluorobenzyl)- 200.057.14 85.71 85.71 1H-indazol-3-yl]-4-(4- methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4- ylamino)-benzamide Betaine hydrochloride 66.5019.00 28.50 28.50 Isomalt 37.50 10.71 16.07 16.07 Microcrystallinecellulose, 24.90 7.11 10.67 10.67 NF (Avicel ® PH-200 LM) Pregelatinizedstarch, NF 17.50 5.00 7.50 7.50 (Starch 1500) Colloidal silicon dioxide1.80 0.51 0.77 0.77 (Cab-O-Sil ®) Magnesium stearate, NF 1.80 0.51 0.770.77 (HyQual ® 5712 Powder) Total 350.00 100.00 150.00 150.00

The betaine hydrochloride was ground in a mortar and pestle before use.TheN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidewas milled before use. Approximately the same volumes of isomalt andmagnesium stearate were added to a weighing boat and stirred together.Approximately the same volumes of isomalt and colloidal silicon dioxidewere added to a weighing boat and stirred together in a plastic bag. Theremaining isomalt, pregelatinized starch, microcrystalline cellulose andbetaine hydrochloride were added to a plastic bag and briefly mixedtogether. All theN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidewas added to the plastic bag and the resulting mixture was mixed by handin the plastic bag for about two minutes. The resulting mixture in theplastic bag was screened through a 40-mesh screen and was added to aV-blender. The mixture of magnesium stearate and isomalt from theweighing boat were also added to the V-blender and the resulting mixturewas blended for about 3 minutes at 25 rpm.

Tablets were prepared from the above mixture using tooling for capletshaving dimensions measuring 0.2500×0.7500. The flow of the powder in thehopper was generally poor and frequent stirring in the hopper wasrequired.

Example 5

A pharmaceutical composition comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideand betaine hydrochloride was prepared as follows.

Actual Target weight amount per Target per dosage unit weight per batchComponent (mg) % w/w batch (g) (g) N-[5-(3,5-difluorobenzyl)- 200.044.44 66.67 66.67 1H-indazol-3-yl]-4-(4- methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4- ylamino)-benzamide Betaine hydrochloride 66.5014.78 22.17 22.17 Isomalt 91.00 20.22 30.33 30.33 microcrystallinecellulose, 61.00 13.56 20.33 20.33 NF (Avicel ® PH-200 LM)Croscarmellose sodium 4.50 1.00 1.50 1.50 (Ac-Di-Sol ® SD-711)Pregelatinized starch, NF 22.50 5.00 7.50 7.50 (Starch 1500) Colloidalsilicon dioxide 2.25 0.50 0.75 0.75 (Cab-O-Sil ®) Magnesium stearate, NF2.25 0.50 0.75 0.75 (HyQual ® 5712 Powder) Total 450.00 100.00 150.00150.00

The betaine hydrochloride was ground in a mortar and pestle before use.TheN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidewas milled before use. Approximately the same volumes of isomalt andmagnesium stearate were added to a weighing boat and stirred together.Approximately the same volumes of isomalt and colloidal silicon dioxidewere added to a weighing boat and stirred together in a plastic bag. Theremaining isomalt, pregelatinized starch, microcrystalline cellulose,croscarmellose sodium, and betaine hydrochloride were added to a plasticbag and mixed together for about one minute. All theN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidewas added to the plastic bag and the resulting mixture was mixed by handin the plastic bag. The resulting mixture in the plastic bag wasscreened through a 40-mesh screen and was added to a V-blender. Themixture of magnesium stearate and isomalt from the weighing boat werealso added to the V-blender and the resulting mixture was blended forabout 3 minutes at 25 rpm.

Tablets were prepared from the above mixture using tooling for capletshaving dimensions measuring 0.2500×0.7500. The sticking of the powder tothe tooling was an issue and required the use of magnesium stearate foreach compression and the powder had to be stirred in the hopper twiceduring compression (tablets #3 and #29).

Example 6

A pharmaceutical composition comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideand betaine hydrochloride was prepared as follows.

Target amount per Target Actual dosage weight per weight per Componentunit (mg) % w/w batch (g) batch (g) N-[5-(3,5-difluorobenzyl)- 200.044.44 66.67 66.67 1H-indazol-3-yl]-4-(4- methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4- ylamino)-benzamide Betaine hydrochloride 66.5014.78 22.17 22.17 Isomalt 94.00 20.889 31.33 31.33 microcrystallinecellulose, 62.50 13.89 20.83 20.83 NF (Avicel ® PH-200 LM)Pregelatinized starch, NF 22.50 5.00 7.50 7.50 (Starch 1500) Colloidalsilicon dioxide 2.25 0.50 0.75 0.75 (Cab-O-Sil ®) Magnesium stearate, NF2.25 0.50 0.75 0.75 (HyQual ® 5712 Powder) Total 450.00 100.00 150.00150.00

The betaine hydrochloride was ground in a mortar and pestle before use.TheN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidewas milled before use. Approximately the same volumes of isomalt andmagnesium stearate were added to a weighing boat and stirred together.Approximately the same volumes of isomalt and colloidal silicon dioxidewere added to a weighing boat and stirred together in a plastic bag. Theremaining isomalt, pregelatinized starch, microcrystalline cellulose,and betaine hydrochloride were added to a plastic bag and mixed togetherfor about one minute. All theN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidewas added to the plastic bag and the resulting mixture was mixed by handin the plastic bag. The resulting mixture in the plastic bag wasscreened through a 40-mesh screen and was added to a V-blender. Themixture of magnesium stearate and isomalt from the weighing boat werealso added to the V-blender and the resulting mixture was blended forabout 3 minutes at 25 rpm.

Tablets were prepared from the above mixture using tooling for capletshaving dimensions measuring 0.2500×0.7500. The sticking of the powder tothe tooling was an issue and required swabbing of the tooling withmagnesium stearate on every tablet compression. In addition, the weightof the resulting tablets was variable and required some stirring of thepowder in the hopper.

Example 7

A pharmaceutical composition comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideand betaine hydrochloride was prepared as follows.

Target amount per Target Actual dosage weight per weight per Componentunit (mg) % w/w batch (g) batch (g) First LayerN-[5-(3,5-difluorobenzyl)- 200.0 44.44 66.67 66.671H-indazol-3-yl]-4-(4- methyl-piperazin-1-yl)-2- (tetrahydro-2H-pyran-4-ylamino)-benzamide Isomalt 78.25 17.39 26.08 26.08 Pregelatinizedstarch, NF 11.25 2.50 3.75 3.75 (Starch 1500) Colloidal silicon dioxide2.25 0.50 0.75 0.75 (Cab-O-Sil ®) Magnesium stearate, NF 2.25 0.50 0.750.75 (HyQual ® 5712 Powder) Total 292.88 65.08 97.63 97.63 Second LayerBetaine hydrochloride 66.50 14.78 22.17 22.17 Isomalt 78.25 17.39 26.0826.08 Pregelatinized starch, NF 11.25 2.50 3.75 3.75 (Starch 1500)Magnesium stearate, NF 1.13 0.25 0.38 0.38 (HyQual ® 5712 Powder) Totalfor second layer 157.12 Overall total 450.00 100.00 150.00 150.00

The betaine hydrochloride was ground in a mortar and pestle before use.TheN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidewas milled before use. Approximately the same volumes of isomalt andmagnesium stearate were added to a weighing boat and stirred togetherfor layer #1. Approximately the same volumes of isomalt and colloidalsilicon dioxide were added to a weighing boat and stirred together forlayer #1.

For layer #2, the betaine hydrochloride, isomalt, and pregelatinizedstarch were added to a plastic bag, mixed by hand and then added to aV-blender. About the same volume of isomalt and magnesium were mixedtogether by stirring and the resulting mixture was also added to theV-blender and the mixture was blended for about 3 minutes at 25 rpm.

For layer #1, the mixture of colloidal silicon dioxide and isomalt wereadded to a plastic bag and mixed by shaking. To the bag were added theremaining isomalt, pregelatinized starch and the mixture was shaken. Allof theN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidewas added to the bag, the bag was shaken and the resulting mixture wasadded to a V-blender. The pre-mixed isomalt and magnesium stearate wasadded to the V-blender. The resulting mixture was removed from theblender, screened through a 40-mesh screen, added back into the blenderand blended for about 3 minutes at 25 rpm.

The blends were weighed out for subject layers for each tablet usingtooling measuring 0.2500×0.7500: first layer was about 292.88 mg and thesecond layer was about 157.12 mg. The tablets were compressed using aCarver press with a force of about 400 pounds for the first layer andabout 1400 pounds for the finished tablet. Magnesium stearate was dustedonto the upper and lower punches prior to loading the powder into each.

Example 8

A pharmaceutical composition comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideand fumaric acid was prepared as follows.

Amount Component per Capsule (mg)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4- 200.0methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4- ylamino) benzamideFumaric acid 50.0 Pre-gelatinized starch 70.0 Mannitol 125.5 Fumedsilica 2.25 Magnesium stearate 2.25 Total 450

N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidewas screened through 60 mesh sieve, the designated amount was weighed,and was transferred to a blend container. The fumaric acid was milled sothat it flowed through a 60-mesh screen, the desired amount was weighedand was transferred to a blend container. The two components were mixedfor approximately 1 minute. The pre-gelatinized starch, fumed silica,and a half portion of the mannitol were added to the blend container.The resulting mixture was blended for approximately 1 minute and wasscreened through a 40-mesh screen. The magnesium stearate and theremainder of the mannitol were added to a separate container, blendedfor approximately 1 minute, screened through a 40-mesh screen, added tothe first mixture and the combined mixture was blended for about 5minutes.

The resulting mixture was filled into #00 capsules. All capsules werefilled in small-scale capsule filling trays apparatus. Capsule fillingwas based on volumetric filling and dependent on the tap density of theblend material. The 200 mg dose capsules were filled into size #00capsule shells and required strong tapping of the apparatus to achievethe final fill weight.

Capsule dosage strengths of 50 mg and 100 were also prepared. The blendcomposition for all strengths of the capsules is the same as above, butthe capsule fill weight was adjusted proportionally to achieve therequired dosage strength.

The 100 mg dosage strength capsule was prepared by filling the blenddescribed above into size #1 capsules, and the 50 mg dosage strengthcapsule was filled into size #3 capsules. Packing density was greatestfor the 200 mg strength in size #00 capsules, and requiredcorrespondingly more tapping of the powder to fill the capsules to thedesired weight. Packing density was the least for the 50 mg strength.

Packing Tapping Capsule Capsule Volume Density Required Strength SizeFill wt. (mg) (cc) (g/cc) for Filling 200 mg #00  450 0.95 474 Strong100 mg #1 225 0.5 450 Medium  50 mg #3 112.5 0.3 375 Slight

Representative samples of the 200 mg capsules prepared using theprocedures above were tested for drug release using the USP ApparatusType I Basket Method under the conditions described below.

Dissolution Parameters Media 0.05M sodium acetate, adjusted to pH 4.5Volume 500 mL Stirring speed 50 rpm Bath Temperature 37° C. ApparatusBaskets Sample volume 5 mL Samples Time points 15, 30, 45, 60, 120minutes Detection UV at 300 nM

Representative samples of the 200 mg capsules were tested using theconditions described above and provided the following dissolutionresults that represent the average percent drug release (based onmeasured amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidecontained in the media compared to the total amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidecontained in the capsules. The results below represent the averagedissolution data for two capsules that were tested.

Dissolution (%, Average of 2 Capsules prepared according to Example 8)Time (min) 0 15 30 45 60 120 % release of N-[5-(3,5- 0% 23% 54% 78% 90%96% difluorobenzyl)-1H-indazol-3- yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4- ylamino) benzamide from 200 mg capsulesprepared according to Example 8

Representative 200 mg capsules prepared according to Example 11 weretested under the same dissolution conditions as above and provided thefollowing dissolution results that represent the average percent drugrelease (based on measured amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidecontained in the media compared to the total amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidecontained in the capsules. The results below represent the averagedissolution data for two capsules that were tested.

Dissolution (%, Average of 2 Capsules prepared according to Example 11)Time (min) 0 15 30 45 60 120 % release of N-[5-(3,5- 0% 6% 9% 13% 16%18% difluorobenzyl)-1H- indazol-3-yl]-4-(4- methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4- ylamino)-benzamide from 200 mg capsules preparedaccording to Example 11

A pharmaceutical composition comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideand at least one acidulant released a greater amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideinto the dissolution medium under the similar conditions and at aboutthe same measured time points as a pharmaceutical composition comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide,but not comprising at least one acidulant.

Example 9

The suitability of maleic acid, fumaric acid, citric acid and tartaricacid in admixture withN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidewas investigated.

Dry powder mixtures of each acid in a 1:1 weight ratio withN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidewere prepared. The mixtures were prepared in duplicate for each sample,and stored in open top, 4 mL glass vials at (1) 60° C./dry heat and (2)40° C. and 75% relative humidity (RH). Control samples were includedwhich contained onlyN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide.

After 13 days of storage it was observed that the admixtures comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideand tartaric, citric, and maleic acid at the 40° C. and 75% RH conditionhad partially or completely liquefied. In contrast, the admixturecomprising fumaric acid andN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideand the control samples remained dry at 40° C. and 75% RH remained dry.All admixture samples and the control samples stored at the 60° C. anddry heat condition remained as dry powders.

The excipient compatibility samples and controls were analyzed byhigh-performance liquid chromatography (HPLC) after three months storageat both conditions to evaluate purity and degradation ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide.The HPLC traces analyses were conducted on an Agilent 1100 LC, equippedwith Agilent Diode Array Detector and Chemstation Software using theconditions found in the table below.

Column: Waters SunFire ™ C18, 3.5 μm, 150 × 4.6 mm, part no. 186002554,or equivalent. Column temp.: 10° C. Flow rate: 1 mL/min. Injectionvolume: 10 μL Detection 303 nM for and N-[5-(3,5- wavelengths:difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H- pyran-4-ylamino) benzamide andrelated substances Sample storage temp.: Room temperature Run time: 22minutes Mobile Phases: A: 70% water: 30% Acetonitrile, 0.1%trifluoroacetic acid (TFA) v/v B: 30% water: 70% Acetonitrile, 0.1% TFAv/v

Gradient program Time (min) A (%) B (%) 0 90 10 9 77 23 14 32 68 15 3268 15.10 90 10

The results as measured by HPLC are found below.

Most abundant Most impurity abundant % UV (relative impurity SampleCondition Purity retention) (area %) Tartaric Acid 40° C./75% RH 99.1%0.93 0.16% 60° C. Dry Heat 99.4% 0.84 0.13% Citric Acid 40° C./75% RH98.6% 0.78 0.14% 60° C. Dry Heat 98.3% 0.89 0.45% Maleic Acid 40° C./75%RH 44.6% 0.83 51.3% 60° C. Dry Heat 80.4% 0.85 11.4% Fumaric Acid 40°C./75% RH 98.0% 0.85  1.3% 60° C. Dry Heat 99.2% 0.84 0.18% Control 40°C./75% RH 99.2% 0.84 0.13% 60° C. Dry Heat 99.3% 0.84 0.13%

The admixture of maleic acid andN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideshowed poor chemical stability as degradation was observed at bothstorage conditions. The compatibility ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideand citric acid showed only slight increases in impurities at bothstorage conditions. An increase in the impurity at 0.85 RRT was seen forthe fumaric acid sample (1.3% vs. 0.13% for the control) stored at the40° C./75% RH condition, whereas the sample stored at 60° C. showed onlyslight increase in impurities compared to the control. The admixture oftartaric acid andN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideshowed excellent chemical stability with no or very little increase inimpurity levels.

Although the admixture ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideand tartaric acid showed acceptable chemical stability, the admixturedemonstrated unacceptable physical instability due to absorption ofmoisture. In contrast, the admixture ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideand fumaric acid did not demonstrate hygroscopicity and maintained andmaintained an acceptable level of chemical stability.

Example 10 Hereinafter Referred to as Pharmaceutical Composition “F2”

A pharmaceutical composition comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideand fumaric acid was prepared as follows.

Amount per Amount Capsule per batch Component (mg) (g)N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4- 200.0 128.00(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H- pyran-4-ylamino)-benzamideFumaric acid, NF 50.0 32.00 Pre-gelatinized starch 70.0 44.80 Mannitol125.5 80.32 Colloidal silicon dioxide, NF 2.25 1.44 Magnesium stearate2.25 1.44 Total 450 288.0

TheN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidewas screened through a 60-mesh sieve and was transferred to the batchmixing container. The fumaric acid was milled in a ball mill at 30revolutions per second for about 2 minutes, screened through a 60-meshsieve and then transferred to the batch mixing container. The mixture ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideand fumaric acid were mixed by hand for about one minute, after whichtime the pre-gelatinized starch, colloidal silicon dioxide and one-halfof the amount of required mannitol were added to the batch container.The resulting mixture was mixed by hand for about one minute. Themagnesium stearate and mannitol were pre-blended through a 40-mesh sieveand then combined with materials in the batch mixing container. Thefinal mixture was blended by hand for approximately 5 minutes.

The resulting mixture was filled into gelatin capsule shells, opaquewhite, size #00. The body and cap of the capsules were separated, thecapsule bodies were placed into a capsule device, ensuring the top ofthe capsule body was flush with the surface of the filling device bymoving the spacer of the device. The powder blend was poured onto thesurface of the filling device, volumetrically filling the body of thecapsules, and scraping the excess powder evenly until all capsule bodiesare filled. The powder was firmly tamped into the shells one time usinga tamper. Additional powder blend was added to fill the remainder of thecapsule and any excess powder was scraped off. The tamping, filling, andscraping procedures were repeated for each capsule until the desiredcapsule fill weight was achieved. The filled capsules were collected ina 10-mesh sieve and were de-dusted by agitating them lightly.

The filled capsule weight range acceptance limits were set at 93% to107%. The average weight of the empty capsule shells was 119.4 mg. Thelow capsule weight limit was set at (0.93×450 mg)+119.4 mg=538 mg. Thehigh capsule weight limit was set at (1.07×450 mg)+119.4 mg=601 mg. Onlythose capsules meeting the weight limits were used in the studydescribed in Example 12.

Example 11 Hereinafter Referred to as Pharmaceutical Composition “F1”

Hard gelatin capsules comprising 50 mg, 100 mg, and 200 mg ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide,but not comprising at least one acidulant, are prepared as follows.

The required amounts of active ingredient and excipients are weighedinto the warehouse dispensing area. The weight ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideand the mannitol are adjusted according to the active desired potency ofthe dosage form. (1) Manually pre-mixN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideand colloidal silicon dioxide into a polyethylene (PE) bag. (2) Theresulting mixture from step 1 is passed through a 0.500 mm screen sizesieve, along with a portion of the pregelatinized starch and mannitoland the resulting materials are collected in a blender. (3) Theresulting mixture from step 2 is further mixed for about 20 minutes at20-25 rpm. (4) The pregelatinized starch and magnesium stearate and arepre-mixed together and are passed through a 0.500 mm screen size sieve.(5) The material from step 4 are mixed together with the materials fromstep 3 and mixed for about 20 minutes at 20-25 rpm. (6) The blendresulting from step 5 is filled into hard gelatin capsules using anautomatic capsule filling machine. Representative formulations ofcapsules comprising 50 mg, 100 mg or 200 mg ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideare shown below.

50 mg capsule representative batch formulation (50 mg F1) Batch formulaAmount per 50 mg (6,000 capsule Components Function capsules) 50 mgN-[5-(3,5- Active   300 g    50 mg difluorobenzyl)-1H- ingredientindazol-3-yl]-4-(4- methyl-piperazin-1-yl)- 2-(tetrahydro-2H-pyran-4-ylamino)-benzamide Mannitol Filler 255.00 g  42.50 mg Pregelatinizedstarch Filler 102.75 g 17.125 mg Colloidal silicon dioxide Glidant 10.50 g  1.750 mg Magnesium stearate Lubricant  6.75 g  1.125 mg Total675.00 g 112.50 mg

100 mg capsule representative batch formulation (100 mg F1) Batchformula Amount per 100 mg (3,600 capsule Components Function capsules)100 mg N-[5-(3,5- Active  360.0 g 100.00 mg difluorobenzyl)-1H-ingredient indazol-3-yl]-4-(4- methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran- 4-ylamino)-benzamide Mannitol Filler 306.00 g 85.00 mg Pregelatinized starch Filler 123.30 g  34.25 mg Colloidalsilicon dioxide Glidant  12.60 g  3.50 mg Magnesium stearate Lubricant 8.10 g  2.25 mg Total 810.00 g 225.00 mg

200 mg capsule representative batch formulation (200 mg F1) Batchformula Amount per 200 mg (4,100 capsule Components Function capsules)200 mg N-[5-(3,5- Active 820.00 g 200.00 mg difluorobenzyl)-1H-ingredient indazol-3-yl]-4-(4- methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran- 4-ylamino)-benzamide Mannitol Filler 697.00 g170.00 mg Pregelatinized starch Filler 280.85 g  68.50 mg Colloidalsilicon dioxide Glidant  28.70 g  7.00 mg Magnesium stearate Lubricant 18.45 g  4.50 mg Total 1845.00 g  450.00 mg

Example 12 Comparative Pharmacokinetic Study of F1 and F2 Formulations

A comparative pharmacokinetic study in healthy, human subjects wasconducted comparing a 200 mg dosage strength of pharmaceuticalcomposition F1 (as described in Example 11) with a 200 mg dosagestrength pharmaceutical composition F2 (as described in Example 10).

Pharmaceutical compositions F1 and F2, along with and lansoprazole, wereadministered orally with approximately 240 mL of water, according to therandomization scheme. Lansoprazole was administered as 30 mglansoprazole delayed-release capsules.

Subjects were randomized into two groups, A and B. Periods 1 and 2 wereconducted as a crossover design under fasting conditions where allsubjects received F1 and F2. In Period 3, subjects received the sameN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideformulation as they received in Period 2, but under fed conditions. Arepresentative summary of Periods 1, 2, and 3 and the pharmaceuticalcompositions subjects in groups A and B will receive in each Period isfound below.

Subject Group Period 1 (fasted) Period 2 (fasted) Period 3 (fed) A F1 F2F2 B F2 F1 F1

In each period, multiple oral daily doses of lansoprazole wereadministered for 9 consecutive days with a single oral dose ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideadministered concomitantly on Day 4 under fasting (Periods 1 and 2) orfed (Period 3) conditions. PK sampling forN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideand its metabolite, M5, was conducted for 120 hours followingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideadministration.

The washout period was at least 8 days between each dose ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide.

In order to ensure a full panel of subjects (up to 24 subjects in eachstudy part), prior toN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidedosing on day 4, subjects, including standbys (3 replacement subjects ineach dosing group to account for possible dropouts following the safetyevaluations on day 3) received a dose of lansoprazole on days 1 to 3.Lansoprazole administration on days 1 to 9 was conducted in the morning,approximately 1.5 hours prior to administration of either F1 or F2 athour 0 on day 4.

Subjects were randomized and received 3 out of 4 treatments in one ofthe following sequences: ABD or BAC (i.e., Periods 1 and 2 wereconducted as a crossover design under fasting conditions [Treatments Aand B]). In Period 3, subjects received the sameN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideformulation as they received in Period 2, but under fed conditions[Treatment C or D]). Each subject received each of the 3 assignedtreatments on one occasion.

Treatments A and C utilized 200 mg strength F1 capsules.

Treatments B and D utilized 200 mg F2 capsules.

Treatments A, B, C, and D were as follows:

Treatment A: 30 mg lansoprazole (1×30 mg capsule), for 9 consecutivedays (within ±1 hour of dosing time on Day 1), with 800 mg F1 (4×200 mgcapsules) administered under fasting conditions 1.5 hours afteradministration of lansoprazole on Day 4.

Treatment B: 30 mg lansoprazole (1×30 mg capsule), for 9 consecutivedays (within ±1 hour of dosing time on Day 1), with 800 mg F2 (4×200 mgcapsules) administered under fasting conditions 1.5 hours afteradministration of lansoprazole on Day 4.

Treatment C: 30 mg lansoprazole (1×30 mg capsule), for 9 consecutivedays (within ±1 hour of dosing time on Day 1), with 800 mg F1 (4×200 mgcapsules) administered 30 minutes after the start of a high-fatbreakfast on Day 4. On Day 4, lansoprazole was administeredapproximately 1 hour prior to the start of the high-fat meal.

Treatment D: 30 mg lansoprazole (1×30 mg capsule) following an overnightfast, for 9 days (within ±1 hour of dosing time on Day 1), with 800 mgF2 (4×200 mg capsules) administered 30 minutes after the start of ahigh-fat breakfast on Day 4. On Day 4, lansoprazole was administeredapproximately 1 hour prior to the start of the high-fat meal.

For all procedures scheduledpost-N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide dosing, time points were relative to the time ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidedosing (i.e., Hour 0 on Day 4).

For all subjects, blood samples were collected in blood collection tubescontaining sodium heparin at scheduled time points. Sampling time-pointswere relative to the time ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidedosing (i.e., Hour 0 on Day 4). Blood sampling for pharmacokineticmeasurements were scheduled for the following times (in hours) (all timepoints were measured as relative toN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidedosing, i.e., hour 0 on day 4 of the study): 0, 0.5, 1, 2, 3, 4, 5, 6,8, 12, 24, 36, 48, 72, 96, and 120.

Subject plasma samples were analyzed for the presence ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideand a metabolite ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideusing analytical methods known to those of ordinary skill in the art.

All subjects who received at least one dose ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideand had evaluable PK data made up the PK Population and was used for allPK analyses. The following PK parameters were calculated forN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidein plasma, as appropriate: AUC_(0-t), AUC_(0-inf), AUC % extrap,C_(max), T_(max), t½, CL/F, and Vz/F.

The PK parameters AUC_(0-t), AUC_(0-inf), and C_(max) forN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidewere analyzed using analysis of variance (ANOVA) model to calculate thegeometric least squares mean (LSM) ratio using natural log-transformeddata. A 90% confidence interval (CI) was constructed around the ratio ofthe geometric mean for the three PK parameters forN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide.

Formulation F1 was used as the reference for all relativebioavailability analysis. Fasted dosing was used as the reference forfood effect analysis. The following assessments were done: (1) therelative bioavailability ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidein two formulations under fasting conditions were evaluated by comparingTreatment B versus Treatment A; and (2) the effect of food on each ofthe twoN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideformulations F1 and F2, were evaluated by comparing (a) for F 1,Treatment C versus Treatment A (within the same treatment sequence), and(b) for F2, Treatment D versus Treatment B (within the same treatmentsequence).

The results of the study are shown in the tables below. All values,except T_(max), are reported as the mean value (% CV). The T_(max)values are reported as the median value and the range. For example, forformulation F1, the median T_(max) for 23 subjects in the fasted statewas about 5 hours, with a range of about 2 hours to about 8 hours.

Formulation F1 Formulation F2 T_(max)* C_(max) AUC₀₋₂₄ AUC_(∞) t_(1/2)T_(max)* C_(max) AUC₀₋₂₄ AUC_(∞) t_(1/2) Period Food N (hr) (nM) (nM ·hr) (nM · hr) (hr) N (hr) (nM) (nM · hr) (nM · hr) (hr) 1 & 2 FastedMean 23 5 623 9390 26700 29.7 24 5 2110 28900 59600 25.2 CV % (2-8) 107118 108 67.9 (2-6) 24 24.3 31.3 29.8

Formulation F1 Formulation F2 T_(max)* C_(max) AUC₀₋₂₄ AUC_(∞) t_(1/2)T_(max)* C_(max) AUC₀₋₂₄ AUC_(∞) t_(1/2) Period Food N (hr) (nM) (nM ·hr) (nM · hr) (hr) N (hr) (nM) (nM · hr) (nM · hr) (hr) 2 Fasted Mean 115 637 8760 26600 33.1 12 5 2080 30800 68800 29.2 CV % (2-8)  84.8 89.284.6 86.4 (4-6)  21.4 21.7 27.9 17.9 3 Fed Mean 11 8 2550 37300 8860028.1 12 8 2560 40400 102000 27 CV % (5-12) 35.5 30 32.6 26.8 (5-12) 20.119.5 28.3 16.6

Additional analysis was conducted to evaluate fixed dosing by bodyweight, or adjusted dosing based on body surface area. At 800 mg fixeddose, a total of 23 healthy subjects were evaluated with body weightsranging from 55 to 106 kg (median 74 kg) and BSA ranging from 1.57 to2.28 mg/m² (median 1.79 mg/m²). Total exposure ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidedid not correlate with body weight or body surface area, suggesting theviability of fixed dosing.

Example 13 Referred to Herein as “F2A”

A pharmaceutical composition comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideand betaine hydrochloride was prepared as follows.

Target amount per Target Actual dosage unit weight per weight perComponent (mg) batch (g) batch (g) N-[5-(3,5-difluorobenzyl)-1H- 200.0222.22 222.23 indazol-3-yl]-4-(4-methyl- piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)- benzamide Betaine hydrochloride 82.0091.11 91.11 Isomalt 124.00 137.78 137.78 Pregelatinized starch, NF 35.0038.89 38.89 (Starch 1500) Colloidal silicon dioxide 4.50 5.00 5.00Magnesium stearate, NF 4.50 5.00 5.00 Total 450.00 500.00 500.01

TheN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidewas screened through a 60-mesh sieve and was transferred to the batchmixing container. The betaine hydrochloride was ground with a mortar andpestle, screened through a 60-mesh sieve and then transferred to thebatch mixing container. The mixture ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideand betaine hydrochloride were mixed by hand for about one minute, afterwhich time the pre-gelatinized starch, colloidal silicon dioxide andone-half of the amount of required isomalt were added to the batchcontainer. The resulting mixture was mixed by hand for about one minute.The magnesium stearate and the remaining isomalt were pre-blendedthrough a 40-mesh sieve and then combined with materials in the batchmixing container. The final mixture was blended by hand forapproximately 5 minutes.

The resulting mixture was filled into gelatin capsule shells, opaquewhite, size #00. The body and cap of the capsules were separated, thecapsule bodies were placed into a capsule device, ensuring the top ofthe capsule body was flush with the surface of the filling device bymoving the spacer of the device. The powder blend was poured onto thesurface of the filling device, volumetrically filling the body of thecapsules, and scraping the excess powder evenly until all capsule bodiesare filled. The powder was firmly tamped into the shells one time usinga tamper. Additional powder blend was added to fill the remainder of thecapsule and any excess powder was scraped off. The tamping, filling, andscraping procedures were repeated for each capsule until the desiredcapsule fill weight was achieved. The filled capsules were collected ina 10-mesh sieve and were de-dusted by agitating them lightly.

The filled capsule weight range acceptance limits were set at 93% to107%. The average weight of the empty capsule shells was 119.4 mg. Thelow capsule weight limit was set at (0.93×450 mg)+119.4 mg=538 mg. Thehigh capsule weight limit was set at (1.07×450 mg)+119.4 mg=601 mg. Onlythose capsules meeting the weight limits were used in subsequentstudies.

Example 14 Comparative Pharmacokinetic Study of F2A

A comparative pharmacokinetic study in healthy, human subjects wasconducted comparing a single dose of F2A with or without the PPIlansoprazole to determine the effects, if any, of the PPI.

Pharmaceutical composition F2A was administered orally at a dosage of800 mg (four 200 mg F2A capsules) with approximately 240 mL of water tohealthy individuals under fasted conditions. Subjects were randomizedinto two groups, E and F. Periods 1 and 2 were conducted as a crossoverdesign under fasting conditions where all subjects received F2A underfasted conditions, but in Period 1 Group A was administered oflansoprazole and Group B was not administered lansoprazole. In Period 2,Group A was not administered lansoprazole and Group B was administeredlansoprazole. In Period 3, the subjects continued the same treatmentfrom Period 2, but under fed conditions. A representative summary ofPeriods 1, 2, and 3 and the pharmaceutical compositions subjects ingroups A and B will receive in each Period is found below.

Subjects were randomized and received 3 out of 4 treatments in one ofthe following sequences: EFH or FEG (i.e., Periods 1 and 2 wereconducted as a crossover design under fasting conditions [Treatments Eand F]). In Period 3, subjects received the sameN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideformulation as they received in Period 2, but under fed conditions[Treatment G or H]). Each subject received each of the 3 assignedtreatments on one occasion.

Treatment E: 800 mg of F2A (4×200 mg capsules) under fasting conditionson Day 4.

Treatment F: 30 mg lansoprazole (1×30 mg capsule) for 8 consecutive days(within ±1 hour of dosing time on Day 1), with 800 mg F2A (4×200 mgcapsules) administered under fasting conditions 1.5 hours afteradministration of lansoprazole on Day 4.

Treatment G: 800 mg F2A (4×200 mg capsules) administered 30 minutesafter the start of a high-fat breakfast on Day 4.

Treatment H: 30 mg lansoprazole (1×30 mg capsule) for 9 consecutive days(within ±1 hour of dosing time on Day 1), with 800 mg F2A (4×200 mgcapsules) administered 30 minutes after the start of a high-fatbreakfast on Day 4. On Day 4, lansoprazole is administered approximately1 hour prior to the start of the high-fat meal.

Subject Group Period 1 (fasted) Period 2 (fasted) Period 3 (fed) E F2Ano lansoprazole F2A w/lansoprazole F2A w/lansoprazole F F2Aw/lansoprazole F2A no lansoprazole F2A no lansoproazole

In each period, up to 12 of the 24 subjects received doses oflansoprazole, which were administered to determine the effect of the PPIbased on the above scheme with a single oral dose ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideadministered concomitantly on Day 4 of each period either under fasting(Periods 1 and 2) or fed (Period 3) conditions. Plasma pharmacokineticsampling forN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideand its metabolite, M5, was conducted for 120 hours followingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideadministration.

The washout period was at least 8 days between each dose ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide.

The washout period was at least 8 days between each dose ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide.

For all procedures scheduledpost-N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide dosing, time points were relative to the time ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidedosing (i.e., Hour 0 on Day 4).

For all subjects, 16 mg ondansetron is administered without water on Day4 of each period prior toN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide dosing, as a prophylactic antiemetic measure.

For all subjects, blood samples were collected in blood collection tubescontaining sodium heparin at scheduled time points. Sampling time-pointswere relative to the time ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidedosing (i.e., Hour 0 on Day 4). Blood sampling for pharmacokineticmeasurements were scheduled for the following times (in hours) (all timepoints were measured as relative toN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidedosing, i.e., hour 0 on day 4 of the study): 0, 0.5, 1, 2, 3, 4, 5, 6,8, 12, 24, 36, 48, 72, 96, and 120.

Subject plasma samples were analyzed for the presence ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideand a metabolite ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideusing analytical methods known to those of ordinary skill in the art.

All subjects who received at least one dose ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideand had evaluable PK data made up the PK Population and was used for allPK analyses. The following PK parameters were calculated forN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidein plasma, as appropriate: AUC_(0-t), AUC_(0-inf), AUC % extrap,C_(max), T_(max), t½, CL/F, and Vz/F.

The PK parameters AUC_(0-t), AUC_(0-inf), and C_(max) forN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidewere analyzed using analysis of variance (ANOVA) model to calculate thegeometric least squares mean (LSM) ratio using natural log-transformeddata. A 90% confidence interval (CI) was constructed around the ratio ofthe geometric mean for the three PK parameters forN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide.Formulation 2A was used as the reference for all relativebioavailability analysis.

The results of the study are shown in the tables below. All values,except T_(max), are reported as the mean value (% CV). The T_(max)values are reported as the median value and the range.

Dose N T_(max) C_(max) AUC_(∞) No PPI 22 Mean 4.0 2670 66000 % CV (2-5)24.0 28.8 W PPI 22 Mean 4.5 1500 39400 % CV (3-6) 30.7 35.2

Following a single dose of F2A at 800 mg (4×200 mg F2A capsules) tohealthy subjects under fasted conditions, F2A was readily absorbed, withdetectable F2A in circulation at 0.5 hr post-dose and reaching medianT_(max) at 4.5 hr with lansoprazole, and 5 hr without lansoprazole. Meanterminal half-life (t_(1/2)) was approximately 24 hours, supporting aonce daily dosing regimen. FIG. 1 depicts a graphical illustrationcomparing the effect of lansoprazole. As seen in FIG. 1, and as shown inthe table above, a clear PPI effect is observed when using F2A withlansoprazole under fasted conditions, where the AUC_(∞) is approximately67% higher without lansoprazole.

In addition to comparing the effects of lansoprazole, the above studywas used to determine the effect of food with F2A treatment by comparingPeriod 2 with Period 3 for each treatment group. Group A received nolansoprazole under fasting conditions in Period 2, and no lansoprazoleunder fed conditions in Period 3. The table below shows the food effectwithout lansoprazole. See also FIG. 2 and FIG. 3.

% CV Average Comparison AUC_(∞) No PPI PPI No PPI PPI Fasted 24 32 6160044300 Fed 32 32 82800 95800

The data indicate that when F2A is administered without lansoprazole,the AUC_(∞) is approximately 25% higher under fed conditions compared tofasted conditions. In addition, the individual difference of AUC_(∞) wasup to 2.5 times greater under fed conditions compared to fastedconditions (FIG. 2).

The effect of PPI co-administration was also evaluated for the F2Aformulation. Mean steady-state exposure of F2A was approximately 40%lower in subjects were co-administered a PPI, compared to subjectsadministered F2A alone. The table below summarizes the effect ofco-administration of PPI on F2A exposure in healthy subjects underfasted conditions.

Geomean Ratio GeoLSM (%) CI90% Parameter N w PPI no PPI (w PPI/no PPI)Lower Upper C_(max) (nm) 22 1439 2609 55 49 62 AUC_(inf) 22 37498 6297260 52 68 (nM · hr)

The food effect was also evaluated for the F2A formulation, both withand without co-administration of a PPI. Without PPI, minimal food effectwas observed, with a fed/fasted geometric mean ratio of 131%. Withco-administration of a PPI, a higher fed/fasted geometric mean ratio of213% was observed. However, the difference in food effect wassignificantly reduced compared to a similar study of the F1 formulation(˜4×) as summarized in the table below.

Geomean Ratio (%) GeoLSM (Fed/ CI90% PPI Parameter N Fed Fasted Fasted)Lower Upper No C_(max) (nm) 12 2468 2477 100 88.1 114 PPI AUC_(inf) 1279019 60113 131 108 160 (nM · hr) W C_(max) (nm) 9 2199 1480 149 122 180PPI AUC_(inf) 9 91392 42457 215 169 269 (nM · hr)

In summary, formulation F2A greatly reduced the inter-subjectvariability and food effect compared to formulation F1. In addition,co-administration of a PPI with formulation F2A results in a 40%reduction of F2A exposure.

The data also show that when F2A is administered with lansoprazole, theAUC_(∞) is approximately 80% greater under fed conditions compared tofasted conditions. The individual difference of AUC_(∞) can be up to 3times greater in fed conditions compared to fasted conditions, as isshown in FIG. 3.

The full results of the study are shown in the tables below. All values,except T_(max), are reported as the mean value (% CV). The T_(max)values are reported as the median value and the range.

Formulation F2A without PPI Formulation F2A with PPI T_(max)* C_(max)AUC₀₋₂₄ AUC_(∞) t_(1/2) T_(max)* C_(max) AUC₀₋₂₄ AUC_(∞) t_(1/2) PeriodFood N (hr) (nM) (nM · hr) (nM · hr) (hr) N (hr) (nM) (nM · hr) (nM ·hr) (hr) 1 Fasted Mean 10 3.5 2860 38300 71400 23.7 12 3.0 1490 1900035200 23.1 CV % (2-5) 28.8 27.3 32.1 15.5 (3-5) 36.1 32.5 36.4 20.6 2Fasted Mean 12 4.0 2510 34300 61600 23.2 10 5.0 1520 22200 44300 24.5 CV% (3-5) 16.2 17.1 23.8 12.1 (3-6) 24.8 26.2 31.6 18.8 1 & 2 Fasted Mean22 4.0 2670 36100 66000 23.4 22 4.5 1500 20400 39400 23.8 CV % (2-5)24.0 23.0 28.8 13.5 (3-6) 30.7 29.8 35.2 19.5

Formulation F2A T_(max)* C_(max) AUC₀₋₂₄ AUC_(∞) t_(1/2) Period Food N(hr) (nM) (nM · hr) (nM · hr) (hr) 2 Fasted Mean 10 5.0 1520 22200 4430024.5 CV % (3-6)  24.8 26.2 31.6 18.8 3 Fed Mean 11 12   2270 36600 9580028.1 CV % (8-12) 26.6 30 31.8 26.8

FIG. 4 summarizes the PK data for F2A under fed conditions with a PPI.

Example 15 Formulation Comparison

The pharmacokinetic data for administration of formulations F1(pharmaceutical composition comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidenot comprising at least one acidulant), F2 (pharmaceutical compositioncomprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidewith fumaric acid as an acidulant) and F2A (pharmaceutical compositioncomprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidewith betaine hydrochloric acid as an acidulant) under fasted or fedconditions with a PPI are compared in the table below.

FASTED % CV Comparison Exposure C_(max) AUC_(∞) C_(max) AUC_(∞) F1 107108 623 26700 F2 24 31 2110 59600 F2A 31 35 1500 39400

FED % CV Comparison Exposure C_(max) AUC_(∞) C_(max) AUC_(∞) F1 36 302550 88600 F2 20 28 2560 102000 F2A 27 32 2270 95800

In general, exposure is higher under fed conditions, and high-fat isbetter than medium-fat conditions. In addition, exposure is higherwithout the administration of a PPI. Both F2 and F2A improvedinter-subject variability significantly compared to F1 under fasteddosing in the presence of a PPI, and exposure trends are higher for F2Athan for F 1, but not to a statistically significant level. All threeformulations provide similar inter-subject variability and absoluteexposure under fed conditions, when a high-fat meal was used.

Example 16 Dose Comparisons

Pharmacokinetic parameters were evaluated for dosing with food forformulation F1 following continuous dosing of F1 at doses of 100, 200,400, and 800 mg/m²/day. As shown in the table below, F1 exposure (Cmaxand AUC) increased with the dose in a dose-proportional manner between100 mg/m² and 400 mg/m². Exposure trended approximately two times highercompared with Day 1 at each dose level. At 800 mg/m², exposure of F1 iscomparable to 400 mg/m² dosing, and showed similar accumulation on Day14. Lower exposure was seen on Day 28 as compared to Day 14, likely dueto a combination of research variables.

T_(max) ^(a) AUC₀₋₂₄ Dose Day N Subject (h) C_(max) (nM) (nM · h) 100mg/m² 1 5 Mean 6 549 7500    CV % 4-8 37.5 28.6 28 3 Mean 4 114020400    CV % 2-8 19.6 24.4 200 mg/m² 1 5 Mean 6 1450 21000    CV % 4-850.4 40.5 28 5 Mean 4 2120 33600    CV % 2-6 39.6 45.7 400 mg/m² 1 10 Mean 4 2730 41300^(b )    CV % 2-8 43.3 52.5 28 7 Mean 4 440089400^(c )    CV % 2-6 44.6 37.7 800 mg/m² 1 8 Mean 5 3770 53200    CV %4-8 51.5 55.1 14 5 Mean 6 5770 101000     CV %  2-24 63.5 70.7 28  3^(d)Mean 4 3840 62400    CV % 2-8 33.5 44.1 ^(a)Median and range of T_(max)reported; ^(b)N = 9; ^(c)N = 6; ^(d)all are at 600 mg dosing.

Example 17

A pharmaceutical composition comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideand tartaric acid is prepared as follows.

Amount Per Amount per Component Capsule (mg) Batch (g) Materials forstep (a) N-[5-(3,5-difluorobenzyl)-1H-indazol-3- 200.0 132.0yl]-4-(4-methyl-piperazin-1-yl)-2- (tetrahydro-2H-pyran-4-ylamino)-benzamide Lactose Anhydrous, DT, NF 124.15 74.49 Hypromellose, USP(Methocel E5) 18.00 10.80 Croscarmellose Sodium, NF/EP (Ac-Di- 11.256.750 Sol) (L) Tartaric Acid, USP/NF 80.85 53.36 Magnesium Stearate,Non-Bovine 2.250 1.350 Hyqual, NF, EP Materials for step (b)Croscarmellose Sodium, NF/EP (Ac-Di- 11.25 6.750 Sol) MagnesiumStearate, Non-Bovine 2.250 1.350 Hyqual, NF, EP Total 450.0 270.0 (a).Each of the components in the table above for step (a) is weighed out asset forth in the table for each batch of capsules. TheN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideis passed through a 30 mesh hand screen. Each of the lactose,hypromellose, and croscarmellose is passed through a 20 mesh hand screeninto a container. The tartaric acid is passed through a FrewittOscillator with a 0.4 mm opening screen and collected into a separatecontainer. TheN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide,lactose, hypromellose, and croscarmellose, and tartaric acid are placedinto a V-blender and the mixture is blended for 10 minutes. Themagnesium stearate is passed through a 20 mesh screen and added to theV-blender and the resulting mixture is blended for 5 minutes. Theresulting blend is placed into a suitable container lined withdouble-polyethylene bags. The mixture is granulated using TFC Lab MicroRoller Compactor using a roller speed of 2,500 rpm and a rollerhydraulic pressure of 500 psi until the fines are minimized. A 20-meshscreen is used to screen out fines which are the added to thegranulation mixture. The mixture is then passed through a FrewittOscillator equipped with a 0.80 mm screen. (b). The croscarmellose andmagnesium stearate in the table above for step (b) are weighed andpassed through a 20-mesh screen. The mixture from step (a) above isadded to a V-blender along with the extra-granular croscarmellose andblended for 10 minutes. The magnesium stearate is then added to themixture and the resulting mixture is blended in a V-blender for 5minutes. c. Approximately 450 mg of the blend from step (b) is filledinto gelatin capsule shells or HPMC capsule shells and the resultingcapsules are manually de-dusted as needed.

Example 18

A pharmaceutical composition comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideand tartaric acid is prepared utilizing the ingredients in the amountslisted below and according to a procedure similar to that disclosed inExample 17, except that the TFC Lab Micro Roller Compactor was used instep (a) was set at a speed of 2,500 rpm and a hydraulic pressure of 750psi, and the Frewitt Oscillator used in step (a) was equipped with a0.80 mm screen.

Amount Per Amount per Component Capsule (mg) Batch (g) Materials forstep (a) N-[5-(3,5-difluorobenzyl)-1H-indazol-3- 200.0 132.0yl]-4-(4-methyl-piperazin-1-yl)-2- (tetrahydro-2H-pyran-4-ylamino)-benzamide Silicified Microcrystalline Cellulose 124.15 74.49 (ProsolvSMCC 90) Hypromellose, USP (Methocel E5) 18.00 10.80 CroscarmelloseSodium, NF/EP (Ac-Di- 11.25 6.750 Sol) (L) Tartaric Acid, USP/NF 80.8548.51 Magnesium Stearate, Non-Bovine Hyqual, 2.250 1.350 NF, EPMaterials for step (b) Croscarmellose Sodium, NF/EP (Ac-Di- 11.25 6.750Sol) Magnesium Stearate, Non-Bovine Hyqual, 2.250 1.350 NF, EP Total450.0 270.0

Example 19

A pharmaceutical composition comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideand tartaric acid is prepared utilizing the ingredients in the amountslisted below and according to a procedure similar to that disclosed inExample 17, except that except that the TFC Lab Micro Roller Compactorwas used in step (a) was set at a speed of 2,500 rpm and a hydraulicpressure of 750 psi, and the Frewitt Oscillator used in step (a) wasequipped with a 0.80 mm screen.

Amount Per Amount per Component Capsule (mg) Batch (g) Materials forstep (a) N-[5-(3,5-difluorobenzyl)-1H-indazol- 200.0 132.03-yl]-4-(4-methyl-piperazin-1-yl)-2- (tetrahydro-2H-pyran-4-ylamino)-benzamide Mannitol, USP 90.00 54.00 (Pearlitol 100SD) MicrocrystallineCellulose 34.15 20.49 (Avicel PH 102) Hypromellose, USP (Methocel E5)18.00 10.80 Croscarmellose Sodium, NF/EP (Ac- 11.25 6.750 Di-Sol) (L)Tartaric Acid, USP/NF 80.85 48.51 Magnesium Stearate, Non-Bovine 2.2501.350 Hyqual, NF, EP Materials for step (b) Croscarmellose Sodium, NF/EP(Ac- 11.25 6.750 Di-Sol) Magnesium Stearate, Non-Bovine 2.250 1.350Hyqual, NF, EP Total 450.0 270.0

Example 20

A pharmaceutical composition comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideand tartaric acid is prepared utilizing the ingredients in the amountslisted below and according to a procedure similar to that disclosed inExample 17, except that except that the TFC Lab Micro Roller Compactorwas used in step (a) was set at a speed of 2,500 rpm and a hydraulicpressure of 750 psi, and the Frewitt Oscillator used in step (a) wasequipped with a 0.80 mm screen.

Amount Amount Per per Component Capsule (mg) Batch (g) Materials forstep (a) N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]- 200.0 132.04-(4-methyl-piperazin-1-yl)-2-(tetrahydro- 2H-pyran-4-ylamino)-benzamideDicalcium Phosphate Anhydrous (A-Tab) 90.00 54.00 MicrocrystallineCellulose 34.15 20.49 (Avicel PH 102) Hypromellose, USP (Methocel E5)18.00 10.80 Croscarmellose Sodium, NF/EP (Ac-Di-Sol) 11.25 6.750 (L)Tartaric Acid, USP/NF 80.85 48.51 Magnesium Stearate, Non-Bovine Hyqual,2.250 1.350 NF, EP Materials for step (b) Croscarmellose Sodium, NF/EP(Ac-Di-Sol) 11.25 6.750 Magnesium Stearate, Non-Bovine Hyqual, 2.2501.350 NF, EP Total 450.0 270.0

Example 21 Hereinafter Referred to as Pharmaceutical Composition “F05”

A pharmaceutical composition comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideand tartaric acid was prepared as follows.

Amount per Capsule Component % w/w (mg) Intragranular ComponentsN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4- 44.44 200.00methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4- ylamino)-benzamideLactose Anhydrous 32.44 146.00 Hydroxypropyl Methylcellulose 4.00 18.00Crospovidone 2.78 12.50 Tartaric Acid 9.56 43.00 Magnesium Stearate 0.562.50 Extragranular Components Microcrystalline Cellulose 2.97 13.37Crospovidone 2.50 11.25 Colloidal Silicon Dioxide 0.25 1.13 MagnesiumStearate 0.50 2.25 Total 100.0 450.00

The tartaric acid was screened through a 30-mesh screen. A blender wascharged with the lactose,N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide,hydroxypropyl methylcellulose, intragranular crospovidone, and screenedtartaric acid and pre-blended for 250 revolutions. The resulting mixturewas screened through a 30-mesh screen. The blender was charged with thescreened pre-mixture, which was then blended for 250 revolutions. Theintragranular magnesium stearate was then screened through a 20-meshscreen and charged into the blender, and blended into the pre-mixturefor 125 revolutions. The resulting pre-blend was then roller compactedand milled through a 0.8-mm screen. The microcrystalline cellulose,extragranular crospovidone, and colloidal silicon dioxide was thenscreened through a 20-mesh screen. The blender was charged with themilled roller compacted pre-blend and the screened microcrystallinecellulose, extragranular crospovidone, and colloidal silicon dioxide,and then blended for 250 revolutions. The extragranular magnesiumstearate was screened through a 20-mesh screen and charged into theblender. All components were final blended for 125 revolutions.

The resulting mixture was filled into HPMC capsule shells, opaque white,size #0. The powder blend was filled into the capsules to achieve thetarget fill weight, using an H&K 400 Encapsulator. The filled capsuleswere polished using a capsule deduster, passed through a metal detector,and passed through a weight sorter.

The fill weight range acceptance limits were set at 95% to 105%. Theweight sorting target range acceptable limits were set at 95% to 105%.Only those capsules meeting the weight limits were used in the studydescribed in Example 24.

Example 22 Hereinafter Referred to as Pharmaceutical Composition “F06”

A pharmaceutical composition comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideand tartaric acid was prepared utilizing the ingredients in the amountslisted below and according to a procedure similar to that disclosed inExample 21.

Amount per Capsule Component % w/w (mg) Intragranular ComponentsN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4- 44.44 200.00methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4- ylamino)-benzamideLactose Anhydrous 28.89 130.00 Hydroxypropyl Methylcellulose 4.00 18.00Crospovidone 2.78 12.50 Tartaric Acid 13.11 59.00 Magnesium Stearate0.56 2.50 Extragranular Components Microcrystalline Cellulose 2.97 13.37Crospovidone 2.50 11.25 Colloidal Silicon Dioxide 0.25 1.13 MagnesiumStearate 0.50 2.25 Total 100.0 450.00

In some embodiments, composition of a capsule for F06 is as follows:

Amount Component % w/w per Capsule (mg) Capsule, HPMC, Size 0, OrangeOpaque 1 each Body and Orange Opaque Cap Titanium Dioxide 1.52021.37-1.55 Hypromellose QSP 100 QSP 90-102 FD&C Yellow #6 0.57740.52-0.59 QSP = Quantité Suffisante Pour” (Quality Sufficient For)

Alternatively, a manufacturing process for pharmaceutical compositionF06 and its encapsulation using the above-described capsule is disclosedin Example 26.

Example 23 Hereinafter Referred to as Pharmaceutical Composition “F07”

A pharmaceutical composition comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideand tartaric acid was prepared utilizing the ingredients in the amountslisted below and according to a procedure similar to that disclosed inExample 21.

Amount per Capsule Component % w/w (mg) Intragranular ComponentsN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4- 44.44 200.00methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4- ylamino)-benzamideLactose Anhydrous 25.33 114.00 Hydroxypropyl Methylcellulose 4.00 18.00Crospovidone 2.78 12.50 Tartaric Acid 16.67 75.00 Magnesium Stearate0.56 2.50 Extragranular Components Microcrystalline Cellulose 2.97 13.37Crospovidone 2.50 11.25 Colloidal Silicon Dioxide 0.25 1.13 MagnesiumStearate 0.50 2.25 Total 100.0 450.00

Example 24 Comparative Pharmacokinetic Study of F05, F06, and F07Formulations

A comparative pharmacokinetic study in healthy, human subjects wasconducted comparing a 600 mg dosage strength of pharmaceuticalcomposition F05 (as described in Example 20), with a 600 mg dosagestrength of pharmaceutical composition F06 (as described in Example 21),with a 600 mg dosage strength of pharmaceutical composition F07 (asdescribed in Example 22), and compared with a 600 mg dosage strength ofpharmaceutical composition similar to F2A (as described in Example 13),except that theN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidewas milled prior to mixing with the excipients and encapsulating theresulting pharmaceutical composition.

Pharmaceutical compositions F05, F06, F07, and milled F2A wereadministered orally with approximately 240 mL of water, according to therandomization scheme.

Subjects were randomized into four sequences, ABCDE, BDACF, CADBG, andDCBAH. Periods 1, 2, 3, and 4 were conducted as a crossover design underfasting conditions where all subjects received a single, oral dose ofone of four different formulations (F05, F06, F07, or F2A). In Period 5,subjects received a single, oral dose of only one formulation comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideas per the randomization schedule, administered 30 minutes after thestart of a high-fat, high-calorie meal (described below as “fed” or “fedconditions”). Following the administration of each respective dose ofthe formulation to each subject on day 1 of each period, pharmacokineticsamples were taken for 120 hours post-administration in order to measurethe amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideand its des-methyl metabolite. On day 1 of each dosing period, a singledose of 16 mg ondansetron was administered without water approximately30 to 45 minutes prior to administration of the respective formulationas a prophylactic, antiemetic agent. Additional doses of ondansetronwere administered approximately 8 to 12 hours following dosing of therespective administration at the discretion of the investigator. Therewas a washout period in each subject of at least 9 days between doses ofthe respective formulations.

A representative summary of Periods 1, 2, 3, 4 and 5 and thepharmaceutical compositions subjects in each sequence will receive ineach Period is found below.

Subject Period 1 Period 2 Period 3 Period 4 Period 5 Group (fasted)(fasted) (fasted) (fasted) (fed) ABCDE F05 F06 F07 F2A F2A BDACF F06 F2AF05 F07 F07 CADBG F07 F05 F2A F06 F06 DCBAH F2A F07 F06 F05 F05

Treatments A and H utilized three 200 mg strength F05 capsules.

Treatments B and G utilized three 200 mg strength F06 capsules.

Treatments C and F utilized three 200 mg strength F07 capsules.

Treatments D and E utilized three 200 mg strength F2A capsules.

Treatments A, B, C, D, E, F, G, and H were as follows:

For all procedures scheduledpost-N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide dosing, time points were relative to the time ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidedosing (i.e., Hour 0 on Day 1).

For all subjects, blood samples were collected at scheduled time points.Sampling time-points were relative to the time ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidedosing (i.e., Hour 0 on Day 1). Blood sampling for pharmacokineticmeasurements were scheduled for the following times (in hours) (all timepoints were measured as relative toN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidedosing, i.e., hour 0 on day 4 of the study): 0, 0.5, 1, 2, 3, 4, 5, 6,8, 12, 24, 36, 48, 72, 96, and 120.

Subject plasma samples were analyzed for the presence ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideand the des-methyl metabolite ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideusing analytical methods known to those of ordinary skill in the art.

All subjects who received at least one dose ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideand had evaluable PK data made up the PK Population and was used for allPK analyses. Samples from all subjects were assayed even if the subjectsdid not complete the study. All subjects who complied sufficiently withthe protocol and displayed an evaluable PK profile (e.g., exposure totreatment, availability of measurements and absence of major protocolviolations) was included in the statistical summary of PK parameters.Inclusion in the statistical analysis of any subject who vomited within8 hours after dosing of the respective formulation, i.e., a period oftime equal to two times the mean tmax of entrectinib were evaluated atthe time of analysis. Additionally, in the case of insufficient washout,subjects with a predose concentration that exceeded 5% of the Cmax forthe treatment being tested were considered to have unevaluable PK andwere excluded from PK summary statistics and bioequivalence assessmentfor that treatment. Average bioequivalence comparison methodology wasused in comparing treatments received by the same subjects. In order toprevent confounding of data, only subjects that had evaluable PK in bothcomparison treatments were used for analysis.

The following PK parameters were calculated forN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidein plasma, as appropriate: AUC_(0-t), AUC_(0-inf), C_(max), T_(max).

The PK parameters AUC_(0-t), AUC_(0-inf), and C_(max) forN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidewere analyzed using analysis of variance (ANOVA) model to calculate thegeometric least squares mean (LSM) ratio using natural log-transformeddata. A 90% confidence interval (CI) was constructed around the ratio ofthe geometric mean for the three PK parameters forN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide.

Formulation F2A was used as the reference for all relativebioavailability analysis. Fasted dosing was used as the reference forfood effect analysis. The following assessments were done: (1) therelative bioavailability ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidein four formulations under fasting conditions were evaluated bycomparing Treatment A versus Treatment D, Treatment B versus TreatmentD, and Treatment C versus Treatment D; (2) the effect of food on each ofthe fourN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideformulations F05, F06, F07, and F2A, were evaluated by comparing (a) forF05, Treatment A versus Treatment H (within the same treatmentsequence), (b) for F06, Treatment B versus Treatment G (within the sametreatment sequence), (c) for F07, Treatment C versus Treatment F (withinthe same treatment sequence), and (d) for F2A, Treatment D versusTreatment E (within the same treatment sequence); and (3) the relativebioavailability ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamidein four formulations under fed conditions were evaluated by comparingTreatment F versus Treatment E, Treatment G versus Treatment E, andTreatment H versus Treatment E.

The results of the study are shown in the tables below. All values arereported as the mean value (% CV). For example, for formulation F05, themedian T_(max) for 48 subjects in the fasted state was about 3.58 hours,with a CV % of about 31.4%.

T_(max) C_(max) AUC₀₋₁₂₀ AUC_(∞) Treatment Formulation Food N (hr) (nM)(nM * hr) (nM * hr) A F05 Fasted Mean 48 3.58 2150 52900 53800 CV % 31.430.2 34.8 35.5 B F06 Fasted Mean 48 3.54 2260 56100 57200 CV % 31.9 34.241.7 42 C F07 Fasted Mean 48 3.67 2300 57200 58300 CV % 29.9 27.4 34.235.1 D F2A milled Fasted Mean 48 3.44 2340 57600 58800 CV % 28.1 28.1 3940.3

T_(max) C_(max) AUC₀₋₁₂₀ AUC_(∞) Treatment Formulation Food N (hr) (nM)(nM * hr) (nM * hr) H F05 Fed Mean 11 5 2440 58800 59400 CV % 8.94 25.733.9 34.2 G F06 Fed Mean 12 5.83 2600 71800 73300 CV % 22.9 15 17.9 19 FF07 Fed Mean 12 5.42 2400 64400 65700 CV % 22.9 17 20.4 21.3 E F2Amilled Fed Mean 12 5.25 2350 63200 64200 CV % 20.1 22.8 31.4 32.1

Example 25 Hereinafter Referred to as Pharmaceutical Composition“F06-100”

A pharmaceutical composition comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamideand tartaric acid was prepared utilizing the ingredients in the amountslisted below and according to a procedure similar to that disclosed inExample 21.

Amount per Capsule Component % w/w (mg) Intragranular ComponentsN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4- 44.44 100.00methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4- ylamino)-benzamideLactose Anhydrous 28.89 65.00 Hydroxypropyl Methylcellulose 4.00 9.00Crospovidone 2.78 6.25 Tartaric Acid 13.11 29.50 Magnesium Stearate 0.561.25 Extragranular Components Microcrystalline Cellulose 2.97 6.685Crospovidone 2.50 5.625 Colloidal Silicon Dioxide 0.25 0.565 MagnesiumStearate 0.50 1.125 Total 100.0 225.00

In some embodiments, composition of a capsule for F06-100 is as follows:

Amount Component % w/w per Capsule (mg) Capsule, HPMC, Size 2, Yellow 1each Opaque Body and Yellow Opaque Cap Titanium Dioxide 1.4584 0.83-0.98Hypromellose QSP 100 QSP 57-65 FDA/E172 Yellow Iron Oxide 0.23070.13-0.15 QSP = Quantité Suffisante Pour” (Quality Sufficient For)

Alternatively, a manufacturing process for pharmaceutical compositionF06-100 and its encapsulation using the above-described capsule isdisclosed in Example 26.

Example 26 Manufacturing Process for Capsules Containing F06 and F06-100

The manufacturing process for capsules containing F06 and F06-100 wasdivided into four parts: 1) manufacture of the intragranular blend, 2)manufacture of the extragranular blend, 3) encapsulation, and 4) capsulepackaging. The first two parts (manufacture of the intragranular blendand manufacture of the extragranular blend) form the dry granulationblending process of F06 and F06-100 capsules. The dry granulationblending process consisted of the following steps: Pre-blending, rollercompaction, milling, blending, final blending (lubrication), andencapsulation as detailed below:

1) Manufacture of the Intragranular Blend:

-   -   1. Charge        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide,        Lactose Anhydrous, Hypromellose, Tartaric acid, Crospovidone        (Portion 1) into a tote blender and blend for approximately 125        revolutions. Screen the pre-blend through a 30-mesh screen.    -   2. Charge the screened pre-blend into the blender and blend for        approximately 250 revolutions. Screen the pre-blend through a        30-mesh screen.    -   3. Charge the screened pre-blend into the blender and blend for        approximately additional 250 revolutions.    -   4. Screen Magnesium Stearate (Portion 1) through a 20-mesh        screen and add to the blender and blend for 125 revolutions.    -   5. Roller compact the blend to obtain the compacted material.    -   6. Pass the roller compacted material through a 0.80 mm screen.

2) Manufacture of the Extragranular Blend:

-   -   1. Using the yield of the milled material, adjust and reweigh        the required quantities of Microcrystalline Cellulose,        Crospovidone (Portion 2), Colloidal Silicon Dioxide, and        Magnesium Stearate (Portion 2).    -   2. Screen the Microcrystalline Cellulose, Crospovidone (Portion        2), Colloidal Silicon Dioxide, and Magnesium Stearate        (Portion 2) through a-20 mesh screen, while keeping the        Magnesium Stearate separate.    -   3. Charge the screened Microcrystalline Cellulose, Crospovidone        (Portion 2), Colloidal Silicon Dioxide, and milled material to        the blender and blend for approximately 250 revolutions.    -   4. Charge the screened Magnesium Stearate to the blender and        blend for approximately 125 revolutions to create the final dry        granulation blend.

3) Encapsulation:

-   -   1. Fill the final dry granulation blend using the encapsulator,        with continuous monitoring, into size 0 or size 2 HPMC capsule        shell for 200-mg and 100-mg strengths, respectively.

4) Packaging:

-   -   1. 100-mg Strength (F06-100): Fill thirty 100-mg capsules into a        40 cc white HDPE bottle with one 0.5-g desiccant canister,        enclosed with a 33 mm white child-resistant caps and induction        heat sealed.    -   2. 200-mg Strength (F06): Fill ninety 200-mg capsules into a 150        cc white HDPE bottle with one 2-g desiccant canister, enclosed        with a 38 mm white child-resistant caps and induction heat        sealed.

Para. A. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant.

Para. B. The pharmaceutical composition of Para. A, wherein said atleast one acidulant is an organic acidulant.

Para. C. The pharmaceutical composition of Para. A, wherein said atleast one acidulant is selected from tartaric acid, maleic acid, fumaricacid, citric acid, and betaine hydrochloride.

Para. D. The pharmaceutical composition of Para. C, wherein said atleast one acidulant is fumaric acid.

Para. E. The pharmaceutical composition of Para. C, wherein said fumaricacid is in a micronized form.

Para. F. The pharmaceutical composition of Para. C, wherein said atleast one acidulant is tartaric acid.

Para. G. The pharmaceutical composition of Para. C, wherein said atleast one acidulant is maleic acid.

Para. H. The pharmaceutical composition of Para. C, wherein said atleast one acidulant is citric acid.

Para. I. The pharmaceutical composition of Para. C, wherein said atleast one acidulant is betaine hydrochloride.

Para. J. The pharmaceutical composition of any one of Paras. A-I,wherein the molar ratio between saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand said at least one acidulant is from about 0.5 to about 2.

Para. K. The pharmaceutical composition of Para. J, wherein said molarratio between saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand said at least one acidulant is from about 0.75 to about 1.75.

Para. L. The pharmaceutical composition of Para. J, wherein said molarratio between saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand said at least one acidulant is from about 1 to about 1.75.

Para. M. The pharmaceutical composition of Para. J, wherein said molarratio between saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand said at least one acidulant is from about 1 to about 1.5.

Para. N. The pharmaceutical composition of Para. J, wherein said molarratio between saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand said at least one acidulant is from about 1.25 to about 1.75.

Para. O. The pharmaceutical composition of Para. J, wherein said molarratio between saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand said at least one acidulant is from about 1 to about 1.5.

Para. P. The pharmaceutical composition of Para. J, wherein said molarratio between saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand said at least one acidulant is about 1.5.

Para. Q. The pharmaceutical composition of any one of Paras. A-P,wherein said pharmaceutical composition is in the form of a tablet orcapsule.

Para. R. The pharmaceutical composition of Para. Q, wherein saidpharmaceutical composition is in the form of a tablet.

Para. S. The pharmaceutical composition of Para. Q, wherein saidpharmaceutical composition is in the form of a capsule.

Para. T. The pharmaceutical composition of any one of Paras. A-S,wherein said pharmaceutical composition comprises from about 25 mg toabout 500 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

Para. U. The pharmaceutical composition of Para. T, wherein saidpharmaceutical composition comprises from about 50 mg to about 450 mg ofsaidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

Para. V. The pharmaceutical composition of Para. T, wherein saidpharmaceutical composition comprises from about 50 mg to about 450 mg ofsaidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

Para. W. The pharmaceutical composition of Para. T, wherein saidpharmaceutical composition comprises from about 50 mg to about 200 mg ofsaidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

Para. X. The pharmaceutical composition of Para. T, wherein saidpharmaceutical composition comprises about 50 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

Para. Y. The pharmaceutical composition of Para. T, wherein saidpharmaceutical composition comprises about 100 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

Para. Z. The pharmaceutical composition of Para. T, wherein saidpharmaceutical composition comprises about 200 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

Para. AA. The pharmaceutical composition of Para. D, wherein theparticle size of said fumaric acid is such that it passes through a60-mesh screen.

Para. AB. The pharmaceutical composition of Para. A, wherein less thanabout 2% of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidedegrades in said pharmaceutical composition after said pharmaceuticalcomposition is stored for 3 months in an open container at 40° C. and75% relative humidity.

Para. AC. The pharmaceutical composition of Para. A, wherein more thanabout 98% of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideis present in said pharmaceutical composition after said pharmaceuticalcomposition is stored for 3 months in an open container at 40° C. and75% relative humidity.

Para. AD. The pharmaceutical composition of Para. A, wherein less thanabout 2% of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidedegrades in said pharmaceutical composition after said pharmaceuticalcomposition is stored for 3 months in an open container at 60° C. and75% relative humidity.

Para. AE. The pharmaceutical composition of Para. A, wherein more thanabout 98% of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideis present in said pharmaceutical composition after said pharmaceuticalcomposition is stored for 3 months in an open container at 60° C. and75% relative humidity.

Para. AF. A pharmaceutical composition comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one pharmaceutically acceptable excipient, wherein saidpharmaceutical composition is in the form of a tablet or capsule, andwherein said tablet or capsule has a dissolution profile wherein atleast about 30% of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidehas been released from said tablet or capsule at about 60 minutes whentested in USP Apparatus Type I Basket Method at 50 rpm in 500 mL ofsodium acetate buffer at a pH of 4.5 and at about 37° C.

Para. AG. The pharmaceutical composition of Para. AF, wherein saidtablet or capsule has a dissolution profile wherein at least about 20%of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidehas been released from said tablet or capsule at about 45 minutes whentested in USP Apparatus Type I Basket Method at 50 rpm in 500 mL ofsodium acetate buffer at a pH of 4.5 and at about 37° C.

Para. AH. The pharmaceutical composition of Para. AF, wherein saidtablet or capsule has a dissolution profile wherein at least about 15%of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidehas been released from said tablet or capsule at about 30 minutes whentested in USP Apparatus Type I Basket Method at 50 rpm in 500 mL ofsodium acetate buffer at a pH of 4.5 and at about 37° C.

Para. AI. A pharmaceutical composition comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one pharmaceutically acceptable excipient, wherein saidpharmaceutical composition is in the form of a tablet or capsule, andwherein said tablet or capsule has a dissolution profile wherein atleast about 50% of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidehas been released from said tablet or capsule at about 60 minutes whentested in USP Apparatus Type I Basket Method at 50 rpm in 500 mL ofsodium acetate buffer at a pH of 4.5 and at about 37° C.

Para. AJ. The pharmaceutical composition of Para. AI, wherein saidtablet or capsule has a dissolution profile wherein at least about 40%of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidehas been released from said tablet or capsule at about 45 minutes whentested in USP Apparatus Type I Basket Method at 50 rpm in 500 mL ofsodium acetate buffer at a pH of 4.5 and at about 37° C.

Para. AK. A solid pharmaceutical composition according to Para. AI,wherein said tablet or capsule has a dissolution profile wherein atleast about 20% of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidehas been released from said tablet or capsule at about 30 minutes whentested in USP Apparatus Type I Basket Method at 50 rpm in 500 mL ofsodium acetate buffer at a pH of 4.5 and at about 37° C.

Para. AL. The pharmaceutical composition of any one of Paras. A-AK,wherein said pharmaceutical composition further comprises mannitol orisomalt.

Para. AM. The pharmaceutical composition of Para. AL, wherein saidpharmaceutical composition further comprises starch.

Para. AN. The pharmaceutical composition of Para. AM, wherein the weightto weight ratio of said mannitol or isomalt to said starch in saidpharmaceutical composition is from about 1 to 1 to about 3 to 1.

Para. AO. The pharmaceutical composition of Para. AN, wherein saidweight to weight ratio of said mannitol or isomalt to said starch insaid pharmaceutical composition is from about 1.5 to 1 to about 3 to 1.

Para. AP. The pharmaceutical composition of Para. AN, wherein saidweight to weight ratio of said mannitol or isomalt to said starch insaid pharmaceutical composition is from about 1.75 to 1 to about 3 to 1.

Para. AQ. The pharmaceutical composition of Para. AN, wherein saidweight to weight ratio of said mannitol or isomalt to said starch insaid pharmaceutical composition is from about 1 to 1 to about 2.5 to 1.

Para. AR. The pharmaceutical composition of Para. AN, wherein saidweight to weight ratio of said mannitol or isomalt to said starch insaid pharmaceutical composition is from about 1 to 1 to about 2 to 1.

Para. AS. The pharmaceutical composition of Para. AN, wherein saidweight to weight ratio of said mannitol or isomalt to said starch insaid pharmaceutical composition is about 2 to 1.

Para. AT. The pharmaceutical composition of Para. AN, wherein saidweight to weight ratio of said mannitol or isomalt to said starch insaid pharmaceutical composition is about 1.8.

Para. AU. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state provides a pharmacokineticprofile in said subject wherein the T_(max) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 2 hours and 6 hoursfollowing said administration of said pharmaceutical composition to saidsubject.

Para. AV. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fed state provides a pharmacokineticprofile in said subject wherein the Tmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 5 hours and 12 hoursfollowing said administration of said pharmaceutical composition to saidsubject.

Para. AW. A pharmaceutical composition comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state at a total dose of about 800mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the C_(max)of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 2080 nM and about 2110 nMfollowing said administration of said pharmaceutical composition to saidsubject.

Para. AX. A pharmaceutical composition comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state at a total dose of about 800mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the C_(max)of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 2080 nM and about 2560 nMfollowing said administration of said pharmaceutical composition to saidsubject.

Para. AY. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state at a total dose of about 800mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the C_(max)of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between 80% to 125% of 2080 nM, basedon a 90 percent confidence interval following said administration ofsaid pharmaceutical composition to said subject.

Para. AZ. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fed state at a total dose of about 800 mgof saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the C_(max)of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between 80% to 125% of 2560 nM, basedon a 90 percent confidence interval following said administration ofsaid pharmaceutical composition to said subject.

Para. BA. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state at a total dose of about 800mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the AUC(0 to24) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 28,900 nM*hr and about30,800 nM*hr following said administration of said pharmaceuticalcomposition to said subject.

Para. BB. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fed rate at a total dose of about 800 mgof saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the AUC(0 to24) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is about 40,400 nM*hr following saidadministration of said pharmaceutical composition to said subject.

Para. BC. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state at a total dose of about 800mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the AUC(0 to24) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is within about 80% to about 125% of30,800 nM*hr at a 90% confidence interval following said administrationof said pharmaceutical composition to said subject.

Para. BD. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fed state at a total dose of about 800 mgof saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideprovides a pharmacokinetic profile in said subject wherein the AUC(0 to24) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is within about 80% to about 125% of40,400 nM*hr at a 90% confidence interval following said administrationof said pharmaceutical composition to said subject.

Para. BE. The pharmaceutical composition of any one of Paras. AA-BD,wherein said pharmaceutical composition is in the form of a tablet orcapsule.

Para. BF. The pharmaceutical composition of Para. BE, wherein saidpharmaceutical composition is in the form of a capsule.

Para. BG. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering a C_(max) of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject of between about 2080 nM and about        2100 nM following administration of said pharmaceutical        composition to said subject in a fasted state, and wherein said        composition comprises a total dose of about 800 mg of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

Para. BH. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering a C_(max) of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject of about 2560 nM following        administration of said pharmaceutical composition to said        subject in a fed state, and wherein said composition comprises a        total dose of about 800 mg of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

Para. BI. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering an AUC(0 to 24) of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject of between about 28,900 nM*hr and        about 30,800 nM*hr following administration of said        pharmaceutical composition to said subject in a fasted state,        and wherein said composition comprises a total dose of about 800        mg of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

Para. BJ. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering an AUC(0 to 24) of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject of about 40,400 nM*hr following        administration of said pharmaceutical composition to said        subject in a fed state, and wherein said composition comprises a        total dose of about 800 mg of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

Para. BK. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering a T_(max) of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject of between about 2 hours and about 6        hours following administration of said pharmaceutical        composition to said subject in a fasted state.

Para. BL. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering a T_(max) of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject of between about 5 hours and about 12        hours following administration of said pharmaceutical        composition to said subject in a fed state.

Para. BM. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering a C_(max) of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject that is between 80% to 125% of 2080        nM, based on a 90 percent confidence interval, following        administration of said pharmaceutical composition to said        subject in a fasted state, and wherein said composition        comprises a total dose of about 800 mg of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

Para. BN. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering a C_(max) of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject that is between 80% to 125% of 2560        nM, based on a 90 percent confidence interval, following        administration of said pharmaceutical composition to said        subject in a fed state, and wherein said composition comprises a        total dose of about 800 mg of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

Para. BO. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering an AUC(0 to 24) of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject that is between 80% to 125% of 30,800        nM*hr, based on a 90 percent confidence interval, following        administration of said pharmaceutical composition to said        subject in a fasted state, and wherein said composition        comprises a total dose of about 800 mg of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

Para. BP. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering an AUC(0 to 24) of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject that is between 80% to 125% of 40,400        nM*hr, based on a 90 percent confidence interval, following        administration of said pharmaceutical composition to said        subject in a fed state, and wherein said composition comprises a        total dose of about 800 mg of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

Para. BQ. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        to a subject that exhibits no food effect.

Para. BR. A pharmaceutical composition comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide,wherein said pharmaceutical composition exhibits no food effect whenadministered to a subject.

Para. BS. The pharmaceutical composition of Para. J, wherein said molarratio between saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand said at least one acidulant is from about 0.5 to about 1.5.

Para. BT. The pharmaceutical composition of Para. J, wherein said molarratio between saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand said at least one acidulant is from about 0.5 to about 1.25.

Para. BU. The pharmaceutical composition of Para. J, wherein said molarratio between saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand said at least one acidulant is from about 0.5 to about 1.

Para. BV. The pharmaceutical composition of Para. J, wherein said molarratio between saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand said at least one acidulant is about 1.2.

Para. BW. The pharmaceutical composition of Para. J, wherein said molarratio between saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand said at least one acidulant is about 0.9.

Para. BX. The pharmaceutical composition of Para. J, wherein said molarratio between saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand said at least one acidulant is about 0.7.

Para. BY. The pharmaceutical composition of Para. T, wherein saidpharmaceutical composition comprises from about 50 mg to about 300 mg ofsaidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

Para. BZ. The pharmaceutical composition of Para. F, wherein theparticle size of said tartaric acid is such that it passes through a30-mesh screen.

Para. CA. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state provides a pharmacokineticprofile in said subject wherein the Tmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 2 hours and 5 hoursfollowing said administration of said pharmaceutical composition to saidsubject.

Para. CB. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state provides a pharmacokineticprofile in said subject wherein the Tmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 2.5 hours and 4.7 hoursfollowing said administration of said pharmaceutical composition to saidsubject.

Para. CC. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state provides a pharmacokineticprofile in said subject wherein the Tmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 2.4 hours and 4.7 hoursfollowing said administration of said pharmaceutical composition to saidsubject.

Para. CD. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state provides a pharmacokineticprofile in said subject wherein the Tmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 2.6 hours and 4.8 hoursfollowing said administration of said pharmaceutical composition to saidsubject.

Para. CE. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fed state provides a pharmacokineticprofile in said subject wherein the Tmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 4 hours and 8 hoursfollowing said administration of said pharmaceutical composition to saidsubject.

Para. CF. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fed state provides a pharmacokineticprofile in said subject wherein the Tmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 4.6 hours and 5.4 hoursfollowing said administration of said pharmaceutical composition to saidsubject.

Para. CG. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fed state provides a pharmacokineticprofile in said subject wherein the Tmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 4.5 hours and 7.2 hoursfollowing said administration of said pharmaceutical composition to saidsubject.

Para. CH. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fed state provides a pharmacokineticprofile in said subject wherein the Tmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 4.2 hours and 6.7 hoursfollowing said administration of said pharmaceutical composition to saidsubject.

Para. CI. A pharmaceutical composition comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state provides a pharmacokineticprofile in said subject wherein the Cmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 1200 nM and 3500 nMfollowing said administration of said pharmaceutical composition to saidsubject.

Para. CJ. A pharmaceutical composition comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state provides a pharmacokineticprofile in said subject wherein the Cmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 1500 nM and about 2800 nMfollowing said administration of said pharmaceutical composition to saidsubject.

Para. CK. A pharmaceutical composition comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state provides a pharmacokineticprofile in said subject wherein the Cmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 1490 nM and about 3030 nMfollowing said administration of said pharmaceutical composition to saidsubject.

Para. CL. A pharmaceutical composition comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state provides a pharmacokineticprofile in said subject wherein the Cmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 1670 nM and about 2930 nMfollowing said administration of said pharmaceutical composition to saidsubject.

Para. CM. A pharmaceutical composition comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fed state provides a pharmacokineticprofile in said subject wherein the Cmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 1500 nM and about 3500 nMfollowing said administration of said pharmaceutical composition to saidsubject.

Para. CN. A pharmaceutical composition comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fed state provides a pharmacokineticprofile in said subject wherein the Cmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 1810 nM and about 3070 nMfollowing said administration of said pharmaceutical composition to saidsubject.

Para. CO. A pharmaceutical composition comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fed state provides a pharmacokineticprofile in said subject wherein the Cmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 2210 nM and about 2990 nMfollowing said administration of said pharmaceutical composition to saidsubject.

Para. CP. A pharmaceutical composition comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fed state provides a pharmacokineticprofile in said subject wherein the Cmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 1990 nM and about 2810 nMfollowing said administration of said pharmaceutical composition to saidsubject.

Para. CQ. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state provides a pharmacokineticprofile in said subject wherein the AUC(0 to 120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 30,000 nM*hr and about85,000 nM*hr following said administration of said pharmaceuticalcomposition to said subject.

Para. CR. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state provides a pharmacokineticprofile in said subject wherein the AUC(0 to 120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 34,100 nM*hr and about71,700 nM*hr following said administration of said pharmaceuticalcomposition to said subject.

Para. CS. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state provides a pharmacokineticprofile in said subject wherein the AUC(0 to 120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 32,500 nM*hr and about79,700 nM*hr following said administration of said pharmaceuticalcomposition to said subject.

Para. CT. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state provides a pharmacokineticprofile in said subject wherein the AUC(0 to 120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 37,100 nM*hr and about77,300 nM*hr following said administration of said pharmaceuticalcomposition to said subject.

Para. CU. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fed state provides a pharmacokineticprofile in said subject wherein the AUC(0 to 120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 35,000 nM*hr and about90,000 nM*hr following said administration of said pharmaceuticalcomposition to said subject.

Para. CV. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fed state provides a pharmacokineticprofile in said subject wherein the AUC(0 to 120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 38,900 nM*hr and about78,700 nM*hr following said administration of said pharmaceuticalcomposition to said subject.

Para. CW. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fed state provides a pharmacokineticprofile in said subject wherein the AUC(0 to 120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 58,900 nM*hr and about84,700 nM*hr following said administration of said pharmaceuticalcomposition to said subject.

Para. CX. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fed state provides a pharmacokineticprofile in said subject wherein the AUC(0 to 120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 51,300 nM*hr and about77,500 nM*hr following said administration of said pharmaceuticalcomposition to said subject.

Para. CY. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state provides a pharmacokineticprofile in said subject wherein the AUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 30,000 nM*hr and about85,000 nM*hr following said administration of said pharmaceuticalcomposition to said subject.

Para. CZ. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state provides a pharmacokineticprofile in said subject wherein the AUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 34,700 nM*hr and about72,900 nM*hr following said administration of said pharmaceuticalcomposition to said subject.

Para. DA. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state provides a pharmacokineticprofile in said subject wherein the AUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 33,200 nM*hr and about81,200 nM*hr following said administration of said pharmaceuticalcomposition to said subject.

Para. DB. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state provides a pharmacokineticprofile in said subject wherein the AUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 37,800 nM*hr and about78,800 nM*hr following said administration of said pharmaceuticalcomposition to said subject.

Para. DC. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fed state provides a pharmacokineticprofile in said subject wherein the AUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 35,000 nM*hr and about90,000 nM*hr following said administration of said pharmaceuticalcomposition to said subject.

Para. DD. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fed state provides a pharmacokineticprofile in said subject wherein the AUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 39,100 nM*hr and about79,700 nM*hr following said administration of said pharmaceuticalcomposition to said subject.

Para. DE. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fed state provides a pharmacokineticprofile in said subject wherein the AUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 59,400 nM*hr and about87,200 nM*hr following said administration of said pharmaceuticalcomposition to said subject.

Para. DF. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fed state provides a pharmacokineticprofile in said subject wherein the AUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 51,700 nM*hr and about79,700 nM*hr following said administration of said pharmaceuticalcomposition to said subject.

Para. DG. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state provides a pharmacokineticprofile in said subject wherein the Tmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is within about 80% to about 125% of 3.6hours at a 90% confidence interval following said administration of saidpharmaceutical composition to said subject.

Para. DH. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state provides a pharmacokineticprofile in said subject wherein the Tmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is within about 80% to about 125% of 3.5hours at a 90% confidence interval following said administration of saidpharmaceutical composition to said subject.

Para. DI. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state provides a pharmacokineticprofile in said subject wherein the Tmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is within about 80% to about 125% of 3.7hours at a 90% confidence interval following said administration of saidpharmaceutical composition to said subject.

Para. DJ. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fed state provides a pharmacokineticprofile in said subject wherein the Tmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is within about 80% to about 125% of 5hours at a 90% confidence interval following said administration of saidpharmaceutical composition to said subject.

Para. DK. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fed state provides a pharmacokineticprofile in said subject wherein the Tmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is within about 80% to about 125% of 5.8hours at a 90% confidence interval following said administration of saidpharmaceutical composition to said subject.

Para. DL. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fed state provides a pharmacokineticprofile in said subject wherein the Tmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is within about 80% to about 125% of 5.4hours at a 90% confidence interval following said administration of saidpharmaceutical composition to said subject.

Para. DM. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state provides a pharmacokineticprofile in said subject wherein the Cmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is within about 80% to about 125% of 2150nM at a 90% confidence interval following said administration of saidpharmaceutical composition to said subject.

Para. DN. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state provides a pharmacokineticprofile in said subject wherein the Cmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is within about 80% to about 125% of 2260nM at a 90% confidence interval following said administration of saidpharmaceutical composition to said subject.

Para. DO. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state provides a pharmacokineticprofile in said subject wherein the Cmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is within about 80% to about 125% of 2300nM at a 90% confidence interval following said administration of saidpharmaceutical composition to said subject.

Para. DP. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fed state provides a pharmacokineticprofile in said subject wherein the Cmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is within about 80% to about 125% of 2440nM at a 90% confidence interval following said administration of saidpharmaceutical composition to said subject.

Para. DQ. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fed state provides a pharmacokineticprofile in said subject wherein the Cmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is within about 80% to about 125% of 2600nM at a 90% confidence interval following said administration of saidpharmaceutical composition to said subject.

Para. DR. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fed state provides a pharmacokineticprofile in said subject wherein the Cmax of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is within about 80% to about 125% of 2400nM at a 90% confidence interval following said administration of saidpharmaceutical composition to said subject.

Para. DS. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state provides a pharmacokineticprofile in said subject wherein the AUC(0 to 120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is within about 80% to about 125% of52,900 nM*hr at a 90% confidence interval following said administrationof said pharmaceutical composition to said subject.

Para. DT. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state provides a pharmacokineticprofile in said subject wherein the AUC(0 to 120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is within about 80% to about 125% of56,100 nM*hr at a 90% confidence interval following said administrationof said pharmaceutical composition to said subject.

Para. DU. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state provides a pharmacokineticprofile in said subject wherein the AUC(0 to 120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is within about 80% to about 125% of57,200 nM*hr at a 90% confidence interval following said administrationof said pharmaceutical composition to said subject.

Para. DV. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fed state provides a pharmacokineticprofile in said subject wherein the AUC(0 to 120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is within about 80% to about 125% of58,800 nM*hr at a 90% confidence interval following said administrationof said pharmaceutical composition to said subject.

Para. DW. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fed state provides a pharmacokineticprofile in said subject wherein the AUC(0 to 120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is within about 80% to about 125% of71,800 nM*hr at a 90% confidence interval following said administrationof said pharmaceutical composition to said subject.

Para. DX. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fed state provides a pharmacokineticprofile in said subject wherein the AUC(0 to 120) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is within about 80% to about 125% of64,400 nM*hr at a 90% confidence interval following said administrationof said pharmaceutical composition to said subject.

Para. DY. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state provides a pharmacokineticprofile in said subject wherein the AUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is within about 80% to about 125% of53,800 nM*hr at a 90% confidence interval following said administrationof said pharmaceutical composition to said subject.

Para. DZ. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state provides a pharmacokineticprofile in said subject wherein the AUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is within about 80% to about 125% of57,200 nM*hr at a 90% confidence interval following said administrationof said pharmaceutical composition to said subject.

Para. EA. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fasted state provides a pharmacokineticprofile in said subject wherein the AUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is within about 80% to about 125% of58,300 nM*hr at a 90% confidence interval following said administrationof said pharmaceutical composition to said subject.

Para. EB. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fed state provides a pharmacokineticprofile in said subject wherein the AUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is within about 80% to about 125% of59,400 nM*hr at a 90% confidence interval following said administrationof said pharmaceutical composition to said subject.

Para. EC. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fed state provides a pharmacokineticprofile in said subject wherein the AUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is within about 80% to about 125% of73,300 nM*hr at a 90% confidence interval following said administrationof said pharmaceutical composition to said subject.

Para. ED. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant, wherein said pharmaceutical composition whenadministered to a subject in a fed state provides a pharmacokineticprofile in said subject wherein the AUC(infinity) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is within about 80% to about 125% of65,700 nM*hr at a 90% confidence interval following said administrationof said pharmaceutical composition to said subject.

Para. EE. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering a Tmax of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject of between about 2 hours and about 5        hours following administration of said pharmaceutical        composition to said subject in a fasted state.

Para. EF. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering a Tmax of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject of between about 4 hours and about 6        hours following administration of said pharmaceutical        composition to said subject in a fed state.

Para. EG. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering a Tmax of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject of between about 4 hours and about 8        hours following administration of said pharmaceutical        composition to said subject in a fed state.

Para. EH. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering a Tmax of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject of between about 4 hours and about 7        hours following administration of said pharmaceutical        composition to said subject in a fed state.

Para. EI. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering a Cmax of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject of between about 1500 nM and about        2800 nM following administration of said pharmaceutical        composition to said subject in a fasted state.

Para. EJ. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering a Cmax of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject of between about 1490 nM and about        3030 nM following administration of said pharmaceutical        composition to said subject in a fasted state.

Para. EK. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering a Cmax of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject of between about 1670 nM and about        2930 nM following administration of said pharmaceutical        composition to said subject in a fasted state.

Para. EL. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering a Cmax of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject of between about 1810 nM and about        3070 nM following administration of said pharmaceutical        composition to said subject in a fed state.

Para. EM. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering a Cmax of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject of between about 2210 nM and about        2990 nM following administration of said pharmaceutical        composition to said subject in a fed state.

Para. EN. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering a Cmax of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject of between about 1990 nM and about        2810 nM following administration of said pharmaceutical        composition to said subject in a fed state.

Para. EO. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering an AUC(0 to 120) of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject of between about 34,100 nM*hr and        about 71,700 nM*hr following administration of said        pharmaceutical composition to said subject in a fasted state.

Para. EP. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering an AUC(0 to 120) of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject of between about 32,500 nM*hr and        about 79,700 nM*hr following administration of said        pharmaceutical composition to said subject in a fasted state.

Para. EQ. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering an AUC(0 to 120) of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject of between about 37,100 nM*hr and        about 77,300 nM*hr following administration of said        pharmaceutical composition to said subject in a fasted state.

Para. ER. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering an AUC(0 to 120) of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject of between about 38,900 nM*hr and        about 78,700 nM*hr following administration of said        pharmaceutical composition to said subject in a fed state.

Para. ES. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering an AUC(0 to 120) of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject of between about 58,900 nM*hr and        about 84,700 nM*hr following administration of said        pharmaceutical composition to said subject in a fed state.

Para. ET. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering an AUC(0 to 120) of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject of between about 51,300 nM*hr and        about 77,500 nM*hr following administration of said        pharmaceutical composition to said subject in a fed state.

Para. EU. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering an AUC(infinity) of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject of between about 34,700 nM*hr and        about 72,900 nM*hr following administration of said        pharmaceutical composition to said subject in a fasted state.

Para. EV. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering an AUC(infinity) of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject of between about 33,200 nM*hr and        about 81,200 nM*hr following administration of said        pharmaceutical composition to said subject in a fasted state.

Para. EW. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering an AUC(infinity) of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject of between about 37,800 nM*hr and        about 78,800 nM*hr following administration of said        pharmaceutical composition to said subject in a fasted state.

Para. EX. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering an AUC(infinity) of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject of between about 39,100 nM*hr and        about 79,700 nM*hr following administration of said        pharmaceutical composition to said subject in a fed state.

Para. EY. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering an AUC(infinity) of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject of between about 59,400 nM*hr and        about 87,200 nM*hr following administration of said        pharmaceutical composition to said subject in a fed state.

Para. EZ. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering an AUC(infinity) of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject of between about 51,700 nM*hr and        about 79,700 nM*hr following administration of said        pharmaceutical composition to said subject in a fed state.

Para. FA. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering an Tmax of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject that is between 80% to 125% of 3.6        hours, based on a 90 percent confidence interval, following        administration of said pharmaceutical composition to said        subject in a fasted state.

Para. FB. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering an Tmax of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject that is between 80% to 125% of 3.5        hours, based on a 90 percent confidence interval, following        administration of said pharmaceutical composition to said        subject in a fasted state.

Para. FC. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering an Tmax of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject that is between 80% to 125% of 3.7        hours, based on a 90 percent confidence interval, following        administration of said pharmaceutical composition to said        subject in a fasted state.

Para. FD. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering an Tmax of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject that is between 80% to 125% of 5        hours, based on a 90 percent confidence interval, following        administration of said pharmaceutical composition to said        subject in a fed state.

Para. FE. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering an Tmax of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject that is between 80% to 125% of 5.8        hours, based on a 90 percent confidence interval, following        administration of said pharmaceutical composition to said        subject in a fed state.

Para. FF. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering an Tmax of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject that is between 80% to 125% of 5.4        hours, based on a 90 percent confidence interval, following        administration of said pharmaceutical composition to said        subject in a fed state.

Para. FG. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering an Cmax of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject that is between 80% to 125% of 2150        nM, based on a 90 percent confidence interval, following        administration of said pharmaceutical composition to said        subject in a fasted state.

Para. FH. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering an Cmax of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject that is between 80% to 125% of 2260        nM, based on a 90 percent confidence interval, following        administration of said pharmaceutical composition to said        subject in a fasted state.

Para. FI. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering an Cmax of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject that is between 80% to 125% of 2300        nM, based on a 90 percent confidence interval, following        administration of said pharmaceutical composition to said        subject in a fasted state.

Para. FJ. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering an Cmax of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject that is between 80% to 125% of 2440        nM, based on a 90 percent confidence interval, following        administration of said pharmaceutical composition to said        subject in a fed state.

Para. FK. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering an Cmax of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject that is between 80% to 125% of 2600        nM, based on a 90 percent confidence interval, following        administration of said pharmaceutical composition to said        subject in a fed state.

Para. FL. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering an Cmax of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject that is between 80% to 125% of 2400        nM, based on a 90 percent confidence interval, following        administration of said pharmaceutical composition to said        subject in a fed state.

Para. FM. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering an AUC(0 to 120) of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject that is between 80% to 125% of 52,900        nM*hr, based on a 90 percent confidence interval, following        administration of said pharmaceutical composition to said        subject in a fasted state.

Para. FN. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering an AUC(0 to 120) of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject that is between 80% to 125% of 56,100        nM*hr, based on a 90 percent confidence interval, following        administration of said pharmaceutical composition to said        subject in a fasted state.

Para. FO. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering an AUC(0 to 120) of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject that is between 80% to 125% of 57,200        nM*hr, based on a 90 percent confidence interval, following        administration of said pharmaceutical composition to said        subject in a fasted state.

Para. FP. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering an AUC(0 to 120) of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject that is between 80% to 125% of 58,800        nM*hr, based on a 90 percent confidence interval, following        administration of said pharmaceutical composition to said        subject in a fed state.

Para. FQ. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering an AUC(0 to 120) of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject that is between 80% to 125% of 71,800        nM*hr, based on a 90 percent confidence interval, following        administration of said pharmaceutical composition to said        subject in a fed state.

Para. FR. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering an AUC(0 to 120) of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject that is between 80% to 125% of 64,400        nM*hr, based on a 90 percent confidence interval, following        administration of said pharmaceutical composition to said        subject in a fed state.

Para. FS. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering an AUC(infinity) of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject that is between 80% to 125% of 53,800        nM*hr, based on a 90 percent confidence interval, following        administration of said pharmaceutical composition to said        subject in a fasted state.

Para. FT. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering an AUC(infinity) of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject that is between 80% to 125% of 57,200        nM*hr, based on a 90 percent confidence interval, following        administration of said pharmaceutical composition to said        subject in a fasted state.

Para. FU. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering an AUC(infinity) of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject that is between 80% to 125% of 58,300        nM*hr, based on a 90 percent confidence interval, following        administration of said pharmaceutical composition to said        subject in a fasted state.

Para. FV. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering an AUC(infinity) of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject that is between 80% to 125% of 59,400        nM*hr, based on a 90 percent confidence interval, following        administration of said pharmaceutical composition to said        subject in a fed state.

Para. FW. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering an AUC(infinity) of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject that is between 80% to 125% of 73,300        nM*hr, based on a 90 percent confidence interval, following        administration of said pharmaceutical composition to said        subject in a fed state.

Para. FX. A pharmaceutical composition, comprising:

-   -   N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        and    -   means for delivering an AUC(infinity) of said        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide        in the plasma of a subject that is between 80% to 125% of 65,700        nM*hr, based on a 90 percent confidence interval, following        administration of said pharmaceutical composition to said        subject in a fed state.

Para. FY. The pharmaceutical composition of any one of Paras. CA-ED,wherein said at least one acidulant is tartaric acid.

Para. FZ. The pharmaceutical composition of any one of Paras. CA-FY,wherein said composition comprises a total dose of about 600 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

Para. GA. The pharmaceutical composition of any one of Paras. CA-FZ,wherein said pharmaceutical composition is in the form of a tablet orcapsule.

Para. GB. The pharmaceutical composition of any one of Paras. CA-GA,wherein said pharmaceutical composition is in the form of a capsule.

Para. GC. The pharmaceutical composition of any one of Paras. A-GBfurther comprising lactose, hypromellose, crospovidone, microcrystallinecellulose, colloidal silicon dioxide, or magnesium stearate, or anycombination of two or more thereof.

Para. GD. The pharmaceutical composition of Para. GC comprising about20% w/w to about 60% w/wN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide,about 5% w/w/to about 20% w/w tartaric acid, about 15% w/w to about 35%w/w lactose, about 1% w/w to about 10% w/w hypromellose, about 1% w/w toabout 5% w/w microcrystalline cellulose, about 1% w/w to about 10% w/wcrospovidone, about 0.05% w/w to about 5% w/w colloidal silicon dioxide,and about 0.1% w/w to about 5% w/w magnesium stearate.

Para. GE. The pharmaceutical composition of Para. GC comprising about40% w/w to about 50% w/wN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide,about 10% w/w/to about 15% w/w tartaric acid, about 25% w/w to about 30%w/w lactose, about 3% w/w to about 5 w/w hypromellose (hydroxypropylmethylcellulose), about 2% w/w to about 4% w/w microcrystallinecellulose, about 4% w/w to about 7% w/w crospovidone, about 0.1% w/w toabout 1% w/w colloidal silicon dioxide, and about 0.5% w/w to about 2%w/w magnesium stearate.

Para. GF. The pharmaceutical composition of any one of Paras. GC-GE,wherein lactose is anhydrous lactose.

Para. GG. The pharmaceutical composition of any one of Paras. A-GF,whereinN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand the at least one acidulant are present in the composition as anadmixture. In other words,N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideis not present in the composition as the salt form of the at least oneacidulant.

Para. GH. A pharmaceutical composition comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide,tartaric acid, anhydrous lactose, hypromellose, microcrystallinecellulose, crospovidone, colloidal silicon dioxide, and magnesiumstearate, wherein the composition is prepared in a method comprising:

-   -   adding        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;        anhydrous lactose; hypromellose; a first portion of        crospovidone; and tartaric acid together and blending to form a        first admixture;    -   sieving the first admixture to form a sieved first admixture;    -   blending the sieved first admixture to form a second admixture;    -   sieving the second admixture to form a sieved second admixture;    -   blending the sieved second admixture to form a third admixture;    -   adding a first portion of magnesium stearate to the third        admixture and blending to form a fourth admixture;    -   compacting and milling the fourth admixture to form a fifth        admixture;    -   adding microcrystalline cellulose, a second portion of        crospovidone, and colloidal silicon dioxide to the fifth        admixture and blending to form a sixth admixture; and    -   adding a second portion of magnesium stearate to the sixth        admixture and blending to form the pharmaceutical composition.

Para. GI. A method of treating a subject having cancer, the methodcomprising administering to the subject the pharmaceutical compositionof any one of Paras. A-GH.

Para. GJ. A method of treating a subject having ALK, ROS1, TrkA, TrkB,or TrkC positive cancer, or a combination thereof, the method comprisingadministering to the subject the pharmaceutical composition of any oneof Paras. A-GH.

Para. GK. A method of treating a subject having ALK positive cancer, themethod comprising administering to the subject the pharmaceuticalcomposition of any one of Paras. A-GH.

Para. GL. A method of treating a subject having ROS1, TrkA, TrkB, orTrkC positive cancer, or a combination thereof, the method comprisingadministering to the subject the pharmaceutical composition of any oneof Paras. A-GH.

Para. GM. A method of treating a subject having ROS1 positive cancer,the method comprising administering to the subject the pharmaceuticalcomposition of any one of Paras. A-GH.

Para. GN. A method of treating a subject having TrkA, TrkB, or TrkCpositive cancer, or a combination thereof, the method comprisingadministering to the subject the pharmaceutical composition of any oneof Paras. A-GH.

Para. GO. A method of treating a subject having TrkA positive cancer,the method comprising administering to the subject the pharmaceuticalcomposition of any one of Paras. A-GH.

Para. GP. A method of treating a subject having TrkB positive cancer,the method comprising administering to the subject the pharmaceuticalcomposition of any one of Paras. A-GH.

Para. GQ. A method of treating a subject having TrkC positive cancer,the method comprising administering to the subject the pharmaceuticalcomposition of any one of Paras. A-GH.

Para. GR. A pharmaceutical composition of any one of Paras. A-GH for usein a method of treating a subject having cancer.

Para. GS. A pharmaceutical composition of any one of Paras. A-GH for usein a method of treating a subject having ALK, ROS1, TrkA, TrkB, or TrkCpositive cancer, or a combination thereof.

Para. GT. A pharmaceutical composition of any one of Paras. A-GH for usein a method of treating a subject having ALK positive cancer.

Para. GU. A pharmaceutical composition of any one of Paras. A-GH for usein a method of treating a subject having ROS1, TrkA, TrkB, or TrkCpositive cancer, or a combination thereof.

Para. GV. A pharmaceutical composition of any one of Paras. A-GH for usein a method of treating a subject having ROS1 positive cancer.

Para. GW. A pharmaceutical composition of any one of Paras. A-GH for usein a method of treating a subject having TrkA, TrkB, or TrkC positivecancer, or a combination thereof.

Para. GX. A pharmaceutical composition of any one of Paras. A-GH for usein a method of treating a subject having TrkA positive cancer.

Para. GY. A pharmaceutical composition of any one of Paras. A-GH for usein a method of treating a subject having TrkB positive cancer.

Para. GZ. A pharmaceutical composition of any one of Paras. A-GH for usein a method of treating a subject having TrkC positive cancer.

Para. HA. Use of the pharmaceutical composition of any one of Paras.A-GH for the preparation of a medicament for the treatment of cancer.

Para. HB. Use of the pharmaceutical composition of any one of Paras.A-GH for the preparation of a medicament for the treatment of ALK, ROS1,TrkA, TrkB, or TrkC positive cancer, or a combination thereof.

Para. HC. Use of the pharmaceutical composition of any one of Paras.A-GH for the preparation of a medicament for the treatment of ALKpositive cancer.

Para. HD. Use of the pharmaceutical composition of any one of Paras.A-GH for the preparation of a medicament for the treatment of ROS1,TrkA, TrkB, or TrkC positive cancer, or a combination thereof.

Para. HE. Use of the pharmaceutical composition of any one of Paras.A-GH for the preparation of a medicament for the treatment of ROS1positive cancer.

Para. HF. Use of the pharmaceutical composition of any one of Paras.A-GH for the preparation of a medicament for the treatment of TrkA,TrkB, or TrkC positive cancer, or a combination thereof.

Para. HG. Use of the pharmaceutical composition of any one of Paras.A-GH for the preparation of a medicament for the treatment of TrkApositive cancer.

Para. HH. Use of the pharmaceutical composition of any one of Paras.A-GH for the preparation of a medicament for the treatment of TrkBpositive cancer.

Para. HI. Use of the pharmaceutical composition of any one of Paras.A-GH for the preparation of a medicament for the treatment of TrkCpositive cancer.

As will be understood by one skilled in the art, for any and allpurposes, such as in terms of providing a written description, allranges provided herein also encompass any and all possible sub-rangesand combinations of sub-ranges thereof. Any listed range can be easilyrecognized as sufficiently describing and enabling the same range beingbroken down into at least equal halves, thirds, quarters, fifths,tenths, etc. As a non-limiting example, each range discussed herein canbe readily broken down into a lower third, middle third and upper third,etc. As will also be understood by one skilled in the art all languagesuch as “up to,” “at least,” “greater than,” “less than,” and the likeinclude the number recited and refer to ranges which can be subsequentlybroken down into sub-ranges as discussed above. Finally, as will beunderstood by one skilled in the art, a range includes each subjectmember. Thus, for example, a group having 1-3 articles refers to groupshaving 1, 2, or 3 articles. Similarly, a group having 1-5 articlesrefers to groups having 1, 2, 3, 4, or 5 articles, and so forth.

Headings, e.g., (a), (b), (i) etc, are presented merely for ease ofreading the specification and claims. The use of headings in thespecification or claims does not require the steps or elements beperformed in alphabetical or numerical order or the order in which theyare presented.

The above description discloses several methods and materials of thepresent disclosure. The embodiments disclosed herein are susceptible tomodifications in the methods and materials, as well as alterations inthe fabrication methods and equipment. Such modifications will becomeapparent to those skilled in the art from a consideration of thisdisclosure or practice of the embodiments provided herein. Consequently,it is not intended that the embodiments disclosed herein be limited tothe specific embodiments provided herein, but that it cover allmodifications and alternatives coming within the true scope and spiritof the disclosure.

All references cited herein, including but not limited to published andunpublished applications, patents, and literature references, areincorporated herein by reference in their entirety and are hereby made apart of this specification. To the extent publications and patents orpatent applications incorporated by reference contradict the disclosurecontained in the specification, the specification is intended tosupersede and/or take precedence over any such contradictory material.

What is claimed is:
 1. A pharmaceutical composition, comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one acidulant.
 2. The pharmaceutical composition of claim1, wherein said at least one acidulant is an organic acidulant.
 3. Thepharmaceutical composition of claim 1, wherein said at least oneacidulant is selected from tartaric acid, maleic acid, fumaric acid,citric acid, and betaine hydrochloride.
 4. The pharmaceuticalcomposition of claim 3, wherein said at least one acidulant is tartaricacid.
 5. The pharmaceutical composition of claim 3, wherein said atleast one acidulant is fumaric acid.
 6. The pharmaceutical compositionof claim 3, wherein said fumaric acid is in a micronized form.
 7. Thepharmaceutical composition of claim 3, wherein said at least oneacidulant is maleic acid.
 8. The pharmaceutical composition of claim 3,wherein said at least one acidulant is citric acid.
 9. Thepharmaceutical composition of claim 3, wherein said at least oneacidulant is betaine hydrochloride.
 10. The pharmaceutical compositionof claim 1, wherein the molar ratio between saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand said at least one acidulant is from about 0.5 to about
 2. 11. Thepharmaceutical composition of claim 1, wherein said pharmaceuticalcomposition is in the form of a tablet or capsule.
 12. Thepharmaceutical composition of claim 1, wherein said pharmaceuticalcomposition comprises from about 25 mg to about 800 mg of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.13. The pharmaceutical composition of claim 4, wherein the particle sizeof said fumaric acid is such that it passes through a 60-mesh screen.14. The pharmaceutical composition of claim 1, wherein less than about2% of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidedegrades in said pharmaceutical composition after said pharmaceuticalcomposition is stored for 3 months in an open container at 40° C. and75% relative humidity.
 15. A pharmaceutical composition comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand at least one pharmaceutically acceptable excipient, wherein saidpharmaceutical composition is in the form of a tablet or capsule, andwherein said tablet or capsule has a dissolution profile wherein atleast about 30% of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidehas been released from said tablet or capsule at about 60 minutes whentested in USP Apparatus Type I Basket Method at 50 rpm in 500 mL ofsodium acetate buffer at a pH of 4.5 and at about 37° C.
 16. Thepharmaceutical composition of claim 1, wherein said pharmaceuticalcomposition further comprises mannitol or isomalt.
 17. Thepharmaceutical composition of claim 16, wherein said pharmaceuticalcomposition further comprises starch.
 18. The pharmaceutical compositionof claim 17, wherein the weight to weight ratio of said mannitol orisomalt to said starch in said pharmaceutical composition is from about1 to 1 to about 3 to
 1. 19. The pharmaceutical composition of claim 1,wherein said pharmaceutical composition when administered to a subjectin a fasted state provides a pharmacokinetic profile in said subjectwherein the T_(max) of saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamidein the plasma of said subject is between about 2 hours and 6 hoursfollowing said administration of said pharmaceutical composition to saidsubject.
 20. The pharmaceutical composition of claim 1, wherein saidpharmaceutical composition exhibits no food effect when administered toa subject.
 21. The pharmaceutical composition of claim 1 furthercomprising lactose, hypromellose, crospovidone, microcrystallinecellulose, colloidal silicon dioxide, or magnesium stearate, or anycombination of two or more thereof.
 22. The pharmaceutical compositionof claim 21 comprising about 20% w/w to about 60% w/wN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide,about 5% w/w/to about 20% w/w tartaric acid, about 15% w/w to about 35%w/w lactose, about 1% w/w to about 10% w/w hypromellose, about 1% w/w toabout 5% w/w microcrystalline cellulose, about 1% w/w to about 10% w/wcrospovidone, about 0.05% w/w to about 5% w/w colloidal silicon dioxide,and about 0.1% w/w to about 5% w/w magnesium stearate.
 23. Thepharmaceutical composition of claim 21 comprising about 40% w/w to about50% w/wN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide,about 10% w/w/to about 15% w/w tartaric acid, about 25% w/w to about 30%w/w lactose, about 3% w/w to about 5% w/w hypromellose (hydroxypropylmethylcellulose), about 2% w/w to about 4% w/w microcrystallinecellulose, about 4% w/w to about 7% w/w crospovidone, about 0.1% w/w toabout 1% w/w colloidal silicon dioxide, and about 0.5% w/w to about 2%w/w magnesium stearate.
 24. The pharmaceutical composition of claim 21,wherein lactose is anhydrous lactose.
 25. The pharmaceutical compositionof claim 1, whereinN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamideand the at least one acidulant are present in the composition as anadmixture.
 26. A pharmaceutical composition comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide,tartaric acid, anhydrous lactose, hypromellose, microcrystallinecellulose, crospovidone, colloidal silicon dioxide, and magnesiumstearate, wherein the composition is prepared in a method comprising:addingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;anhydrous lactose; hypromellose; a first portion of crospovidone; andtartaric acid together and blending to form a first admixture; sievingthe first admixture to form a sieved first admixture; blending thesieved first admixture to form a second admixture; sieving the secondadmixture to form a sieved second admixture; blending the sieved secondadmixture to form a third admixture; adding a first portion of magnesiumstearate to the third admixture and blending to form a fourth admixture;compacting and milling the fourth admixture to form a fifth admixture;adding microcrystalline cellulose, a second portion of crospovidone, andcolloidal silicon dioxide to the fifth admixture and blending to form asixth admixture; and adding a second portion of magnesium stearate tothe sixth admixture and blending to form the pharmaceutical composition.27. A method of treating a subject having cancer, the method comprisingadministering to the subject the pharmaceutical composition of claim 1.28. A method of treating a subject having ROS1, TrkA, TrkB, or TrkCpositive cancer, or a combination thereof, the method comprisingadministering to the subject the pharmaceutical composition of claim 1.